Publications by authors named "David St-Pierre"

38 Publications

Two weeks of western diet disrupts liver molecular markers of cholesterol metabolism in rats.

Lipids Health Dis 2020 Aug 21;19(1):192. Epub 2020 Aug 21.

Department of Exercise Sciences, Université du Québec à Montréal, 141, Avenue Président-Kennedy, C.P. 8888, succursale Centre-Ville, Montréal, Québec, H3C 3P8, Canada.

Background: The present study was designed to test the hypothesis that in the liver, excessive fat accumulation impairs cholesterol metabolism mainly by altering the low-density lipoprotein-receptor (LDL-R) pathway.

Method: Young male Wistar rats were fed standard (SD), high fat (HFD; 60% kcal) or Western (WD; 40% fat + 35% sucrose (17.5% fructose)) diets for 2 or 6 weeks.

Results: Weight gain (~ 40 g) was observed only following 6 weeks of the obesogenic diets (P < 0.01). Compared to the 2-week treatment, obesogenic diets tripled fat pad weight (~ 20 vs 7 g) after 6 weeks. Hepatic triglyceride (TG) levels were greater in response to both the WD and HFD compared to the SD (P < 0.01) at 2 and 6 weeks and their concentrations were greater (P < 0.05) in WD than HFD at 2 weeks. Plasma total cholesterol levels were higher (P < 0.05) in animals submitted to WD. After 2 and 6 weeks, liver expression of LDL-R, proprotein convertase subtilisin/kexin 9 (PCSKk9) and sterol regulatory element binding protein 2 (SREBP2), involved in LDL-cholesterol uptake, was lower in animals submitted to WD than in others treated with HFD or SD (P < 0.01). Similarly, low-density lipoprotein-receptor-related protein 1 (LRP1) and acyl-CoA cholesterol acyltransferase-2 (ACAT-2) mRNA levels were lower (P < 0.01) among WD compared to SD-fed rats. Expression of the gene coding the main regulator of endogenous cholesterol synthesis, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoAR) was reduced in response to WD compared to SD and HFD at 2 (P < 0.001) and 6 (P < 0.05) weeks. Being enriched in fructose, the WD strongly promoted the expression of carbohydrate-response element binding protein (ChREBP) and acetyl-CoA carboxylase (ACC), two key regulators of de novo lipogenesis.

Conclusion: These results show that the WD promptly increased TG levels in the liver by potentiating fat storage. This impaired the pathway of hepatic cholesterol uptake via the LDL-R axis, promoting a rapid increase in plasma total cholesterol levels. These results indicate that liver fat content is a factor involved in the regulation of plasma cholesterol.
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http://dx.doi.org/10.1186/s12944-020-01351-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442981PMC
August 2020

Interplay Between Gut Microbiota and Gastrointestinal Peptides: Potential Outcomes on the Regulation of Glucose Control.

Can J Diabetes 2020 Jun 2;44(4):359-367. Epub 2019 Nov 2.

Department of Exercise Sciences, Université du Québec à Montréal, Montréal, Québec, Canada; Department of Food Science, Université Laval, Montréal, Québec, Canada; Institut de Nutrition et des Aliments Fonctionnels, Université Laval, Montréal, Québec, Canada; CHU Sainte-Justine Research Center, Université de Montréal, Montréal, Québec, Canada. Electronic address:

A host of gastrointestinal (GI) peptides influence the regulation of vital functions, such as growth, appetite, stress, gut motility, energy expenditure, digestion and inflammation, as well as glucose and lipid homeostasis. Hence, impairments in the synthesis/secretion of glucagon-like peptide-1 (GLP-1), leptin, nesfatin-1, glucose-dependent insulinotropic peptide (GIP), ghrelin (acylated and unacylated forms), oxyntomodulin, vasoactive intestinal peptide, somatostatin, cholecystokinin, peptide tyrosine‒tyrosine, GLP-2 and pancreatic polypeptide were previously associated with the development of obesity-related disorders. It is currently emphasized that the beneficial metabolic outcomes associated with the normalization of the gut microbiota (GM) is influenced by increases in GLP-1 and peptide YY secretion as well as by decreases in acylated ghrelin production. These effects are associated with reductions in body weight and adiposity in combination with the normalization of glucose and lipid metabolism. However, important questions remain unanswered regarding how GLP-1, peptide tyrosine‒tyrosine, acylated ghrelin and other metabolically relevant GI peptides interact with the GM to modulate the host's metabolic functions. In addition, it is likely that the GM and other biologically active GI peptides influence metabolic functions, such as glucose control, although the mechanisms remain ill-defined. In this review, we investigate how GM and GI peptides influence glucose metabolism in experimental models, such as germ-free animals and dietary interventions. Emphasis is placed on pathways through which GM and GI peptides could modulate intestinal permeability, nutrient absorption, short-chain fatty acid production, metabolic endotoxemia, oxidative stress and low-grade inflammation.
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http://dx.doi.org/10.1016/j.jcjd.2019.10.006DOI Listing
June 2020

Ethical consideration and feasibility demonstration of high-intensity interval training without the use of electrical shocks in mice with and without doxorubicin exposition.

Am J Cancer Res 2019 1;9(12):2813-2820. Epub 2019 Dec 1.

University Hospital of Montreal, Research Center Montreal, Canada.

Introduction: Most protocols intended to stimulate cardiovascular training in mice use electrical shocks that cause psychological stress and interfere with running performance. The aim of this study was to: 1) demonstrate the feasibility of a two-week high-intensity interval training (HIIT) program without the use of electric shocks in mice and 2) show that HIIT without electric shocks is feasible in the specific context of mice exposed to chemotherapy (i.e., doxorubicin).

Methods: Ten C57bl/6 6-week-old female mice underwent a maximal exercise capacity test before and after two weeks of HIIT (five sessions per week) to measure their maximum running speed. The electrical stimulus was substituted by gently lifting the hind legs of the training mice using a tongue depressor. A second sample of ten C57bl/6 10-week-old female mice receiving a single intravenous injection of 20 mg/kg of doxorubicin underwent a single session of HIIT post-DOX using the same gentle stimulation method.

Results: After two weeks of HIIT without the use of electric shocks, non-treated mice had a significant increase in their maximal speed (4.4 m•min; P = 0.019). In DOX-treated mice, the compliance rate to run went from 100% during the acclimation period prior to doxorubicin treatment to 100% when HIIT was performed after the DOX treatment. Doxorubicin treatment seemed to affect exercise compliance in DOX-treated mice. Our study demonstrated that a two-week HIIT program in non-treated mice and a single HIIT session in DOX-treated mice are feasible.

Conclusion: The use of electric shocks was not required to obtain acceptable exercise compliance and a significant change in mice physical capacity. Our technique to perform a treadmill maximal exercise capacity test was shown to be feasible, even in specific pathological conditions like chemotherapy infusion, and could become a reference for future research protocols aimed at reducing the impact of psychological stress caused by electric shocks in mice. This model of exercise training in mice introduces an alternative to ethical conduct standards in animal research.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943355PMC
December 2019

Timing of high-intensity intermittent exercise affects ad libitum energy intake in overweight inactive men.

Appetite 2019 12 5;143:104443. Epub 2019 Sep 5.

School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil.

The present study sought to clarify the impact of exercise intensity and timing on energy intake and appetite-related blood variables. Fourteen inactive overweight men were included in the study. Firstly, maximal aerobic power (MAP) was measured. Then, participants randomly performed 5 experimental sessions consisting of 30 min of steady-state exercise (SSE) at 50% of MAP, high-intensity intermittent exercise (HIIE) with 30s repetitions at MAP and 30s of passive recovery or no exercise (CTRL). Sessions were performed 1h (SSE and HIIE) or 2.5h (SSE and HIIE) after the consumption of a standardized breakfast. An ad libitum buffet was offered 3.5h after the completion of the breakfast. Absolute energy intake (EI) and relative energy intake (REI) (relative energy intake = energy intake - energy expenditure from exercise) were measured. Appetite (hunger, fullness and desire for specific foods) scores and circulating concentration of insulin and IL-6 were determined at 1h, 1.75h, 2.5h and 3.25h after breakfast while lactate was measured post-exercise. EI was greater after the CTRL session compared to HIIE (5045.9 ± 1873.5 kJ vs. 3716.1 ± 1688.7 kJ). REI was greater for the CTRL session (5045.9 ± 1873.5 kJ) than HIIE (3386.5 ± 1660.1 kJ), HIIE (2508.5 ± 1709.3 kJ) and SSE (3426.6 ± 1788.0 kJ). Higher hunger scores were observed following the CRTL session with respect to those of HIIE. Insulin and IL-6 concentrations were greater after HIIE and SSE with respect to those obtained after HIIE, SSE and CTRL. Lactate concentrations were higher in HIIE and HIIE compared to those of SSE and SSE. These results show that HIIE performed 2.5h after a breakfast reduced appetite (hunger scores) and EI through mechanism that need to be characterized. This approach can be applied to individuals aiming to create an energetic deficit.
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http://dx.doi.org/10.1016/j.appet.2019.104443DOI Listing
December 2019

A Short-Term High-Fat Diet Alters Glutathione Levels and IL-6 Gene Expression in Oxidative Skeletal Muscles of Young Rats.

Front Physiol 2019 10;10:372. Epub 2019 Apr 10.

Département des Sciences de l'Activité Physique, Université du Québec à Montréal (UQAM), Montréal, QC, Canada.

Obesity and ensuing disorders are increasingly prevalent worldwide. High-fat diets (HFD) and diet-induced obesity have been shown to induce oxidative stress and inflammation while altering metabolic homeostasis in many organs, including the skeletal muscle. We previously observed that 14 days of HFD impairs contractile functions of the soleus (SOL) oxidative skeletal muscle. However, the mechanisms underlying these effects are not clarified. In order to determine the effects of a short-term HFD on skeletal muscle glutathione metabolism, young male Wistar rats (100-125 g) were fed HFD or a regular chow diet (RCD) for 14 days. Reduced (GSH) and disulfide (GSSG) glutathione levels were measured in the SOL. The expression of genes involved in the regulation of glutathione metabolism, oxidative stress, antioxidant defense and inflammation were measured by RNA-Seq. We observed a significant 25% decrease of GSH levels in the SOL muscle. Levels of GSSG and the GSH:GSSG ratio were similar in both groups. Further, we observed a 4.5 fold increase in the expression of pro-inflammatory cytokine interleukin 6 (IL-6) but not of other cytokines or markers of inflammation and oxidative stress. We hereby demonstrate that a short-term HFD significantly lowers SOL muscle GSH levels. This effect could be mediated through the increased expression of IL-6. Further, the skeletal muscle antioxidant defense could be impaired under cellular stress. We surmise that these early alterations could contribute to HFD-induced insulin resistance observed in longer protocols.
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http://dx.doi.org/10.3389/fphys.2019.00372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468044PMC
April 2019

Prognostic value of neutrophil to lymphocyte ratio in lung metastasectomy for colorectal cancer.

Eur J Cardiothorac Surg 2019 May;55(5):948-955

Department of Thoracic and Upper Gastrointestinal Surgery, McGill University Health Centre, Montreal, QC, Canada.

Objectives: Neutrophil to lymphocyte ratio (NLR) has been shown to be a promising biomarker in several cancers. Prognostic biomarkers are still needed to define good candidates for lung metastasectomy for colorectal cancer. We aimed to evaluate the role of NLR.

Methods: Data from 574 patients who underwent lung metastasectomy for colorectal cancer in 3 departments of thoracic surgery from 2004 to 2014 were retrospectively reviewed. Overall survival (OS) and the time to pulmonary recurrence (TTPR) were the main end points.

Results: Correlations between NLR and OS (R2 = 0.53), and NLR and TTPR (R2 = 0.389) were significant (P < 0.0001 for both), with corresponding Pearson R of -0.728 (P < 0.0001) and -0.624 (P < 0.0001), respectively. A receiver operating characteristic curve analysis highlighted an NLR cut-off value of 4.05 as the best predictor of OS and TTPR. NLR ≤4.05 was observed in 238 patients (41.4%). In the univariable analysis, the median OS was 117 months for patients with NLR ≤4.05 and decreased to 40 months for patients with NLR >4.05 (P < 0.0001). The median TTPR reached 52 months in case of NLR ≤4.05 and decreased to 12 months in patients with NLR >4.05. In the multivariable analysis, NLR ≤4.05 remained an independent favourable prognostic factor on both OS [hazard ratio [HR] 0.29, 95% confidence interval (CI) 0.167-0.503; P < 0.0001] and TTPR (HR 0.346, 95% CI 0.221-0.54; P < 0.0001). Significant correlations between NLR >4.05 and KRAS (Cramer's V = 0.241, P < 0.0001) and BRAF (Cramer's V = 0.153, P = 0.003) mutations were observed.

Conclusions: NLR is a simple and powerful predictor of outcomes in patients undergoing pulmonary metastasectomy for colorectal cancer.
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http://dx.doi.org/10.1093/ejcts/ezy388DOI Listing
May 2019

Altered Lipid Metabolism Impairs Skeletal Muscle Force in Young Rats Submitted to a Short-Term High-Fat Diet.

Front Physiol 2018 26;9:1327. Epub 2018 Sep 26.

Département des Sciences de l'Activités Physique, Université du Québec à Montréal, Montreal, QC, Canada.

Obesity and ensuing disorders are increasingly prevalent in young populations. Prolonged exposure to high-fat diets (HFD) and excessive lipid accumulation were recently suggested to impair skeletal muscle functions in rodents. We aimed to determine the effects of a short-term HFD on skeletal muscle function in young rats. Young male Wistar rats (100-125 g) were fed HFD or a regular chow diet (RCD) for 14 days. Specific force, resistance to fatigue and recovery were tested in (EDL; glycolytic) and soleus (SOL; oxidative) muscles using an muscle contractility system. Muscle fiber typing and insulin signaling were analyzed while intramyocellular lipid droplets (LD) were characterized. Expression of key markers of lipid metabolism was also measured. Weight gain was similar for both groups. Specific force was decreased in SOL, but not in EDL of HFD rats. Muscle resistance to fatigue and force recovery were not altered in response to the diets. Similarly, muscle fiber type distribution and insulin signaling were not influenced by HFD. On the other hand, percent area and average size of intramyocellular LDs were significantly increased in the SOL of HFD rats. These effects were consistent with the increased expression of several mediators of lipid metabolism in the SOL muscle. A short-term HFD impairs specific force and alters lipid metabolism in SOL, but not EDL muscles of young rats. This indicates the importance of clarifying the early mechanisms through which lipid metabolism affects skeletal muscle functions in response to obesogenic diets in young populations.
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http://dx.doi.org/10.3389/fphys.2018.01327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190893PMC
September 2018

Altered Feeding Behaviors and Adiposity Precede Observable Weight Gain in Young Rats Submitted to a Short-Term High-Fat Diet.

J Nutr Metab 2018 1;2018:1498150. Epub 2018 Apr 1.

Département des Sciences de l'Activité Physique, Université du Québec à Montréal (UQAM), 141 President-Kennedy Ave., Montréal, QC, Canada H2X 1Y4.

Information regarding the early effects of obesogenic diets on feeding patterns and behaviors is limited. To improve knowledge regarding the etiology of obesity, young male Wistar rats were submitted to high-fat (HFD) or regular chow diets (RCDs) for 14 days. Various metabolic parameters were continuously measured using metabolic chambers. Total weight gain was similar between groups, but heavier visceral fat depots and reduced weight of livers were found in HFD rats. Total calorie intake was increased while individual feeding bouts were shorter and of higher calorie intake in response to HFD. Ambulatory activity and sleep duration were decreased in HFD rats during passive and active phase, respectively. Acylated and unacylated ghrelin levels were unaltered by the increased calorie intake and the early changes in body composition. This indicates that at this early stage, the orexigenic signal did not adapt to the high-calorie content of HFD. We hereby demonstrate that, although total weight gain is not affected, a short-term obesogenic diet alters body composition, feeding patterns, satiation, ambulatory activity profiles, and behaviours in a young rat model. Moreover, this effect precedes changes in weight gain, obesity, and ensuing metabolic disorders.
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http://dx.doi.org/10.1155/2018/1498150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901484PMC
April 2018

Immunometabolic Changes in Hepatocytes Arising from Obesity and the Practice of Physical Exercise.

Curr Pharm Des 2018 ;24(27):3200-3209

Exercise and Immunometabolism Research Group, Post-Graduation Program in Movement Sciences, Department of Physical Education, State University of Sao Paulo - UNESP. School of Technology and Sciences, Presidente Prudente, Sao Paulo, Brazil.

Over the recent years, a particular interest was shown towards understanding the roles of excessive hepatic fat accumulation and the development of obesity-related diseases. While hepatic triacylglycerol accumulation seems to be a response to the systemic increase of insulin release, fatty acid metabolites contribute to the progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). It is widely accepted that NAFLD is a polygenic and multifactorial disease under the influence of critical behavioral factors such as overeating and sedentary lifestyles. The progression of the disease is proposed to include the accumulation of lipids in hepatocytes, but liver damage would be mainly initiated through an exaggerated activation of the immune system. This inflammatory response would be triggered by the increase in cytokine production followed by TLR-4 activation and NF-kB pathways. Interestingly, cytokines as IL-1ra, IL-4, IL-6 and IL-10 act as antiinflammatory in response to exercise and thus, could play an important role in the restoration of liver functions in diseased conditions. Strategies for healthy life behaviors including nutrition and regular physical exercise are recommended to counteract the dreadful effects of NAFLD. To beyond the classical effect of exercise for increasing energy expenditure and/or inducing negative energy balance, exercise also prevents and reverses the effects of disorders related to the immunometabolic profile. This suggests that exercise prescription may be an attractive alternative for the prevention of obesity and NAFLD. Thus, this review seeks to shed light on the inflammatory pathways regulating the beneficial effects of physical activity on obesity and NAFLD. We will clarify how physical activity intervenes to normalize inflammatory processes and prevent obesity and NAFLD. Finally, the exercise interventions should be individualized to facilitate behavioral and cognitive strategies in order to promote long-term adherence. A multidisciplinary approach including lifestyles, diet and exercise training interventions is considered as a "best practice" and displays the strongest liver benefits when it occurs simultaneously with weight loss.
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http://dx.doi.org/10.2174/1381612824666180515115550DOI Listing
November 2019

Angiotensin II cyclic analogs as tools to investigate ATR biased signaling mechanisms.

Biochem Pharmacol 2018 08 20;154:104-117. Epub 2018 Apr 20.

Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada. Electronic address:

G protein coupled receptors (GPCRs) produce pleiotropic effects by their capacity to engage numerous signaling pathways once activated. Functional selectivity (also called biased signaling), where specific compounds can bring GPCRs to adopt conformations that enable selective receptor coupling to distinct signaling pathways, continues to be significantly investigated. However, an important but often overlooked aspect of functional selectivity is the capability of ligands such as angiotensin II (AngII) to adopt specific conformations that may preferentially bind to selective GPCRs structures. Understanding both receptor and ligand conformation is of the utmost importance for the design of new drugs targeting GPCRs. In this study, we examined the properties of AngII cyclic analogs to impart biased agonism on the angiotensin type 1 receptor (ATR). Positions 3 and 5 of AngII were substituted for cysteine and homocysteine residues ([SarHcy]AngII, [SarCysHcy]AngII and [SarCys]AngII) and the resulting analogs were evaluated for their capacity to activate the Gq/11, G12, Gi2, Gi3, Gz, ERK and β-arrestin (βarr) signaling pathways via ATR. Interestingly, [SarHcy]AngII exhibited potency and full efficacy on all pathways tested with the exception of the Gq pathway. Molecular dynamic simulations showed that the energy barrier associated with the insertion of residue Phe of AngII within the hydrophobic core of ATR, associated with Gq/11 activation, is increased with [SarHcy]AngII. These results suggest that constraining the movements of molecular determinants within a given ligand by introducing cyclic structures may lead to the generation of novel ligands providing more efficient biased agonism.
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http://dx.doi.org/10.1016/j.bcp.2018.04.021DOI Listing
August 2018

Apple peel polyphenols reduce mitochondrial dysfunction in mice with DSS-induced ulcerative colitis.

J Nutr Biochem 2018 07 21;57:56-66. Epub 2018 Mar 21.

Research Centre, CHU Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada, H3T 1C5; Department of Nutrition, Université de Montréal, Montreal, Quebec, Canada, H3T 1C5; Institute of Nutrition and Functional Foods (INAF), Université Laval, Quebec, Quebec, Canada, G1V 0A6; Department of Anatomy and Cellular Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada, J1H 5N4. Electronic address:

Inflammatory bowel diseases (IBDs) are multifaceted and relapsing immune disorders, which necessitate long-term dependence on powerful drugs. As the use of natural product-based therapies has emerged as a promising intervention, the present study aimed to further characterize dried apple peel powder (DAPP) mechanisms of action and evaluate the preventive and curative effects of DAPP on mitochondrial functions in a murine model. Induction of intestinal inflammation in mice is performed by oral administration of the dextran sodium sulfate (DSS) at 2.5% for 10 days. Doses of DAPP (200 or 400 mg/kg/day) were administered by gavage for 10 days pre- and 1 day after colitis induction simultaneously with DSS treatment for a period of 10 days. The preventive (200 mg/kg/day) and therapeutic (400 mg/kg/day) doses of DAPP limited DSS-induced histological lesions, improved macroscopic parameters and attenuated clinical signs. DAPP at the same conditions reduced massive infiltration of inflammatory cells and concomitantly displayed a robust potential of counteracting inflammation and oxidative stress in DSS mice. Moreover, DAPP partially restored mitochondrial abnormalities related to size, density, redox homeostasis, fatty acid β-oxidation, ATP synthesis, apoptosis and regulatory mitochondrial transcription factors. Our findings demonstrate the preventive and therapeutic impact of DAPP on experimental colitis while underlying the role of mitochondria. They also suggest that this natural DAPP product may represent an interesting candidate for further studies on the prevention/treatment of IBD.
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http://dx.doi.org/10.1016/j.jnutbio.2018.03.008DOI Listing
July 2018

The impact of a short-term high-fat diet on mitochondrial respiration, reactive oxygen species production, and dynamics in oxidative and glycolytic skeletal muscles of young rats.

Physiol Rep 2018 02;6(4)

Département des Sciences de l'activité physique, Faculté des Sciences, UQAM, Montréal, Canada.

Multiple aspects of mitochondrial function and dynamics remain poorly studied in the skeletal muscle of pediatric models in response to a short-term high-fat diet (HFD). This study investigated the impact of a short-term HFD on mitochondrial function and dynamics in the oxidative soleus (SOL) and glycolytic extensor digitorum longus (EDL) muscles in young rats. Young male Wistar rats were submitted to either HFD or normal chow (NCD) diets for 14 days. Permeabilized myofibers from SOL and EDL were prepared to assess mitochondrial respiration and reactive oxygen species (ROS) production. The expression and content of protein involved in mitochondrial metabolism and dynamics (fusion/fission) were also quantified. While no effects of HFD was observed on mitochondrial respiration when classical complex I and II substrates were used, both SOL and EDL of rats submitted to a HFD displayed higher basal and ADP-stimulated respiration rates when Malate + Palmitoyl-L-carnitine were used as substrates. HFD did not alter ROS production and markers of mitochondrial content. The expression of CPT1b was significantly increased in SOL and EDL of HFD rats. Although the expression of UCP3 was increased in SOL and EDL muscles from HFD rats, mitochondrial coupling efficiency was not altered. In SOL of HFD rats, the transcript levels of Mfn2 and Fis1 were significantly upregulated. The expression and content of proteins regulating mitochondrial dynamics was not modulated by HFD in the EDL. Finally, DRP1 protein content was increased by over fourfold in the SOL of HFD rats. Taken altogether, our findings show that exposing young animals to short-term HFD results in an increased capacity of skeletal muscle mitochondria to oxidize fatty acids, without altering ROS production, coupling efficiency, and mitochondrial content. Our results also highlight that the impact of HFD on mitochondrial dynamics appears to be muscle specific.
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http://dx.doi.org/10.14814/phy2.13548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430054PMC
February 2018

Bariatric Surgery-Induced Resolution of Hypertension and Obstructive Sleep Apnea: Impact of Modulation of Body Fat, Ectopic Fat, Autonomic Nervous Activity, Inflammatory and Adipokine Profiles.

Obes Surg 2017 12;27(12):3156-3164

Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada.

Background: Obesity-associated systemic hypertension (HTN) and obstructive sleep apnea (OSA) have multiple pathophysiological pathways including ectopic fat deposition, inflammation, altered adipokine profile, and increased sympathetic nervous activity. We characterized these potential mechanisms in severely obese patients with or without HTN and OSA. We also compared changes of these mechanisms at 12 months following biliopancreatic diversion with duodenal switch (BPD-DS) surgery according to HTN and OSA resolution.

Methods: Sixty-two severely obese patients were evaluated at baseline and 12 months; 40 patients underwent BPD-DS. Blood samples, bioelectrical impedance analysis, computed tomography scan, and 24-h heart rate monitoring were performed. OSA have been determined with polysomnography and HTN with blood pressure measurement and medical file.

Results: Patients with HTN (n = 35) and OSA (n = 32) were older men with higher ectopic fat deposition and lower parasympathetic nervous activity without difference in adipokines and inflammatory markers. Lower reduction in weight was observed in patients with unresolved HTN (-40.9 ± 3.3 kg vs. -55.6 ± 3.8 kg; p = 0.001) and OSA (-41.4 ± 10.7 kg vs. -51.0 ± 15.2 kg; p = 0.006). Visceral adipose tissue reduction was lower in patients with unresolved HTN (-171.0 ± 25.7 cm vs. -274.5 ± 29.0 cm; p = 0.001) in contrast to a trend for lower abdominal subcutaneous adipose tissue reduction in patients with unresolved OSA (-247.7 ± 91.5 cm vs. -390.5 ± 109.1 cm; p = 0.08). At 12 months, parasympathetic activity was lowest in unresolved HTN and OSA patients, without difference in adipokines and inflammatory biomarkers.

Conclusion: Lower ectopic fat mobilization, lower level of parasympathetic nervous activity, and lower subcutaneous adiposity mobilization may play a role in the pathophysiology of unresolved HTN and OSA following BPD-DS surgery.
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http://dx.doi.org/10.1007/s11695-017-2737-zDOI Listing
December 2017

Association between nesfatin-1 levels and metabolic improvements in severely obese patients who underwent biliopancreatic derivation with duodenal switch.

Peptides 2016 12 25;86:6-12. Epub 2016 Sep 25.

Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, Québec, Canada; Faculty of Pharmacy, Université Laval, Québec, Québec, Canada. Electronic address:

Context: Nesfatin-1 is a neuroendocrine peptide with potent anorexigenic activity in rodents. The potential role of nesfatin-1 on the regulation of energy balance, metabolic functions and inflammation is currently debated in obese humans. In the present study, nesfatin-1 fluctuations and their associations with metabolic factors were investigated in severely obese patients who underwent biliopancreatic diversion with duodenal switch (BPD/DS) and severely obese controls (SOC).

Basic Procedures: Sixty severely obese patients who underwent BPD/DS and 15 SOC (matched for BMI and age) were included in the study. Associations between nesfatin-1 levels and body composition, glucose metabolism, lipid profile as well as inflammatory markers were evaluated at baseline and over a post-surgery12-month (12M) period.

Main Findings: Body weight was reduced at 6M and at 12M in BPD/DS patients (P<0.001). Nesfatin-1 levels were reduced at 6M (women: P<0.05) and at 12M (men and women; P<0.001) in BPD/DS patients. At baseline, nesfatin-1 levels negatively correlated with weight, fat (FM) and fat-free mass (FFM) in the whole population (combined BPD/DS and SOC patients). At 12M, nesfatin-1 concentrations positively correlated with weight, FM, fasting insulin, insulin resistance, total cholesterol, LDL-cholesterol, triglyceride and apoB values. At 12M, % changes in nesfatin-1 were positively associated with% changes in weight, FM, FFM, fasting insulin, insulin resistance, total cholesterol, LDL-cholesterol, apoB and C-reactive protein.

Conclusion: Nesfatin-1 levels decrease following BPD/DS-induced weight loss and are significantly associated with parameters of metabolic health.
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http://dx.doi.org/10.1016/j.peptides.2016.09.014DOI Listing
December 2016

Glucose Fluctuations are Not Modulated by the Proportion of Calories from Macronutrients or Spontaneous Total Energy Expenditure in Adults with Cystic Fibrosis.

Can J Diabetes 2016 Oct 7;40(5):389-392. Epub 2016 Jul 7.

Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada; Nutrition Department, Pavillon Liliane-de-Stewart, Université de Montréal, Montréal, Québec, Canada; Montreal Diabetes Research Centre (MDRC), Montréal, Québec, Canada; Cystic Fibrosis Clinic, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada. Electronic address:

Objectives: To determine the modifiable factors affecting glucose variability in people with cystic fibrosis (CF). CF-related diabetes (CFRD) is the most common complication of CF, and its presence increases morbidity and mortality in patients. Patients with CF (with and without CFRD) have potentially harmful glucose fluctuations and glucose excursions when compared to healthy adults. Carbohydrate intake and exercise have been shown to affect glycemia. Therefore, our hypothesis was that the proportion of energy from carbohydrates and total energy expenditure (TEE) would influence glucose fluctuations in adults with CF.

Methods: A cross-sectional study involved 36 patients with CF, in whom continuous glucose monitoring systems were installed. Glucose fluctuations were then quantified using 3 indexes: mean amplitude of glucose excursions, standard deviation and coefficient of variation. Patients filled out a 3-day food diary to quantify energy intake and the proportions of calories from carbohydrates, fats and proteins, and they wore Sensewear Armbands to estimate spontaneous TEE and footsteps walked. Glucose tolerance status was determined using oral glucose tolerance tests.

Results: Patients with CF with normal and impaired glucose tolerance had fewer glucose fluctuations than patients with CFRD (p<0.05). However, linear regression models used to determine whether nutrition or energy expenditure affects glucose fluctuations demonstrated that energy, the proportion of carbohydrates, of fat and of protein, TEE or the number of footsteps walked did not affect glucose fluctuation indexes (p>0.05).

Conclusions: TEE and the proportion of energy from carbohydrates did not affect glucose fluctuations in adults with CF.
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http://dx.doi.org/10.1016/j.jcjd.2016.05.007DOI Listing
October 2016

Effect of an Acute High Carbohydrate Diet on Body Composition Using DXA in Young Men.

Ann Nutr Metab 2015 11;66(4):233-6. Epub 2015 Jul 11.

Department of Exercise Science, Université du Québec à Montréal, Department of Medicine, McGill University, Montreal, Canada.

Aim: The aim of this study is to investigate the effect of a 3-day high-carbohydrate diet (≥75% of total calories) on body composition using dual-energy X-ray absorptiometry (DXA).

Methods: Twenty non-obese young men (age 22.7 ± 2.6 years, BMI 23.5 ± 2.1 kg/m(2)) completed the study. Two DXA tests were performed for the measurement of total body weight, body mass index (BMI), body fat percentage as well as total, appendicular and central lean body mass (LBM) before and after a high-carbohydrate diet for 3 days. In addition, the participants completed a food diary during the 3-day high-carbohydrate diet to determine the mean percentage of carbohydrates consumed from total kilocalories.

Results: The mean percentage of carbohydrate intake over 3 days was 83.7 ± 8.4%. Our results showed a significant increase in total body weight, BMI as well as total and appendicular LBM after the high-carbohydrate diet (p < 0.01). In addition, we observed a strong tendency for lower body fat percentage values after the intervention (p = 0.05). No significant difference was observed for central LBM.

Conclusions: These results indicate that the effect of an acute high carbohydrate diet seems to affect body composition values using DXA, such as total LBM. This study may lead to the need of standardizing a diet prior to using DXA.
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http://dx.doi.org/10.1159/000435840DOI Listing
November 2016

Mitochondrial morphology is altered in atrophied skeletal muscle of aged mice.

Oncotarget 2015 Jul;6(20):17923-37

Département des Sciences de l'Activité Physique, Faculté des Sciences, UQAM, Montréal, Canada.

Skeletal muscle aging is associated with a progressive decline in muscle mass and strength, a process termed sarcopenia. Evidence suggests that accumulation of mitochondrial dysfunction plays a causal role in sarcopenia, which could be triggered by impaired mitophagy. Mitochondrial function, mitophagy and mitochondrial morphology are interconnected aspects of mitochondrial biology, and may coordinately be altered with aging. However, mitochondrial morphology has remained challenging to characterize in muscle, and whether sarcopenia is associated with abnormal mitochondrial morphology remains unknown. Therefore, we assessed the morphology of SubSarcolemmal (SS) and InterMyoFibrillar (IMF) mitochondria in skeletal muscle of young (8-12wk-old) and old (88-96wk-old) mice using a quantitative 2-dimensional transmission electron microscopy approach. We show that sarcopenia is associated with larger and less circular SS mitochondria. Likewise, aged IMF mitochondria were longer and more branched, suggesting increased fusion and/or decreased fission. Accordingly, although no difference in the content of proteins regulating mitochondrial dynamics (Mfn1, Mfn2, Opa1 and Drp1) was observed, a mitochondrial fusion index (Mfn2-to-Drp1 ratio) was significantly increased in aged muscles. Our results reveal that sarcopenia is associated with complex changes in mitochondrial morphology that could interfere with mitochondrial function and mitophagy, and thus contribute to aging-related accumulation of mitochondrial dysfunction and sarcopenia.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627226PMC
http://dx.doi.org/10.18632/oncotarget.4235DOI Listing
July 2015

Crosstalk between intestinal microbiota, adipose tissue and skeletal muscle as an early event in systemic low-grade inflammation and the development of obesity and diabetes.

Diabetes Metab Res Rev 2015 Sep 8;31(6):545-61. Epub 2014 Dec 8.

Department of Biological Sciences, Université du Québec à Montréal, Montreal, Canada, H3C 3P8.

Obesity is associated with a systemic chronic low-grade inflammation that contributes to the development of metabolic disorders such as cardiovascular diseases and type 2 diabetes. However, the etiology of this obesity-related pro-inflammatory process remains unclear. Most studies have focused on adipose tissue dysfunctions and/or insulin resistance in skeletal muscle cells as well as changes in adipokine profile and macrophage recruitment as potential sources of inflammation. However, low-grade systemic inflammation probably involves a complex network of signals interconnecting several organs. Recent evidences have suggested that disturbances in the composition of the gut microbial flora and alterations in levels of gut peptides following the ingestion of a high-fat diet may be a cause of low-grade systemic inflammation that may even precede and predispose to obesity, metabolic disorders or type 2 diabetes. This hypothesis is appealing because the gastrointestinal system is first exposed to nutrients and may thereby represent the first link in the chain of events leading to the development of obesity-associated systemic inflammation. Therefore, the present review will summarize the latest advances interconnecting intestinal mucosal bacteria-mediated inflammation, adipose tissue and skeletal muscle in a coordinated circuitry favouring the onset of a high-fat diet-related systemic low-grade inflammation preceding obesity and predisposing to metabolic disorders and/or type 2 diabetes. A particular emphasis will be given to high-fat diet-induced alterations of gut homeostasis as an early initiator event of mucosal inflammation and adverse consequences contributing to the promotion of extended systemic inflammation, especially in adipose and muscular tissues.
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http://dx.doi.org/10.1002/dmrr.2617DOI Listing
September 2015

Interrelationships between ghrelin, insulin and glucose homeostasis: Physiological relevance.

World J Diabetes 2014 Jun;5(3):328-41

François Chabot, David H St-Pierre, Département de Kinanthropologie, Université du Québec à Montréal, Montréal (Québec), H3C3P8, Canada.

Ghrelin is a 28 amino acid peptide mainly derived from the oxyntic gland of the stomach. Both acylated (AG) and unacylated (UAG) forms of ghrelin are found in the circulation. Initially, AG was considered as the only bioactive form of ghrelin. However, recent advances indicate that both AG and UAG exert distinct and common effects in organisms. Soon after its discovery, ghrelin was shown to promote appetite and adiposity in animal and human models. In response to these anabolic effects, an impressive number of elements have suggested the influence of ghrelin on the regulation of metabolic functions and the development of obesity-related disorders. However, due to the complexity of its biochemical nature and the physiological processes it governs, some of the effects of ghrelin are still debated in the literature. Evidence suggests that ghrelin influences glucose homeostasis through the modulation of insulin secretion and insulin receptor signaling. On the other hand, insulin was also shown to influence circulating levels of ghrelin. Here, we review the relationship between ghrelin and insulin and we describe the impact of this interaction on the modulation of glucose homeostasis.
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http://dx.doi.org/10.4239/wjd.v5.i3.328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058737PMC
June 2014

Amylin stimulates fatty acid esterification in 3T3-L1 adipocytes.

Mol Cell Endocrinol 2013 Feb 20;366(1):99-107. Epub 2012 Dec 20.

Centre de Recherche Institut Universitaire de Cardiologie & Pneumologie de Québec, Department of Medicine, Université Laval, Québec, QC, Canada.

Amylin is co-localized and co-secreted with insulin, however its direct effects on adipocytes are unexplored. In 3T3-L1 preadipocytes, amylin increased thymidine incorporation (174%; p<0.05) and Myc mRNA expression (378%; p<0.01). Amylin supplementation during differentiation enhanced triglyceride accumulation (272%; p<0.001). In 3T3-L1 adipocytes, amylin increased fatty acid uptake (238%; p<0.01) and further potentiated the effects of insulin (insulin 158%; p<0.01, amylin+insulin 335%; p<0.001 vs CTL, p<0.001 vs insulin). By contrast, amylin inhibited glycerol release in 3T3-L1 adipocytes (-50%; p<0.05) and primary adipocytes (-34%; p<0.05). Amylin stimulated cytokine secretion (monocyte chemotactic protein-1+166%, keratinocyte-derived chemokine+174%; both p<0.05) and mRNA expression of PPARγ (163%; p<0.01), C/EBPβ (121%, p<0.05), DGAT1 (157%; p<0.01), FABP4 (122%; p<0.01), and CD36 (122%; p<0.05). In human adipose tissue, mRNA expression of amylin receptor genes (CALCR and RAMP3) correlated with numerous lipid and insulin signaling genes, plasma glucose and HOMA. Altogether amylin directly stimulates fat cells, potentiates the effects of insulin and may influence insulin resistance.
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http://dx.doi.org/10.1016/j.mce.2012.12.008DOI Listing
February 2013

Substance P decreases fat storage and increases adipocytokine production in 3T3-L1 adipocytes.

Am J Physiol Gastrointest Liver Physiol 2013 Feb 20;304(4):G420-7. Epub 2012 Dec 20.

Centre de Recherche Institut Universitaire de Cardiologie and Pneumologie de Quebec and Department of Medicine, Université Laval, Quebec, Quebec, Canada.

Obesity, inflammation, and insulin resistance are closely linked. Substance P (SP), via its neurokinin 1 receptor (NK1R), mediates inflammatory and, possibly, neuroendocrine processes. We examined SP effects on lipid storage and cytokine production in 3T3-L1 adipocytes and adipose tissues. 3T3-L1 adipocytes and preadipocytes express NK1R, and 8 days of SP supplementation during differentiation to 3T3-L1 preadipocytes decreased lipid droplet accumulation. SP (10 nM, 24 h) increased lipolysis in primary adipocytes (138 ± 7%, P < 0.05) and reduced fatty acid uptake (-31 ± 7%, P < 0.05) and mRNA expression of the differentiation-related transcription factors peroxisome proliferator-activated receptor-γ type 2 (-64 ± 2%, P < 0.001) and CCAAT enhancer-binding protein (CEBP)-α (-65 ± 2%, P < 0.001) and the lipid storage genes fatty acid-binding protein type 4 (-59 ± 2%, P < 0.001) and diacylglycerol O-acyltransferase-1 (-45 ± 2%, P < 0.01) in 3T3-L1 adipocytes, while CD36, a fatty acid transporter (+82 ± 19%, P < 0.01), was augmented. SP increased secretion of complement C3 (148 ± 15%, P < 0.04), monocyte chemoattractant protein-1 (156 ± 16%, P < 0.03), and keratinocyte-derived chemokine (148 ± 18%, P = 0.045) in 3T3-L1 adipocytes and monocyte chemoattractant protein-1 (496 ± 142%, P < 0.02) and complement C3 (152 ± 25%, P < 0.04) in adipose tissue and primary adipocytes, respectively. These SP effects were accompanied by downregulation of insulin receptor substrate 1 (-82 ± 2%, P < 0.01) and GLUT4 (-76 ± 2%, P < 0.01) mRNA expression, and SP acutely blocked insulin-mediated stimulation of fatty acid uptake and Akt phosphorylation. Although adiponectin secretion was unchanged, mRNA expression was decreased (-86 ± 8%, P < 0.001). In humans, NK1R expression correlates positively with plasma insulin, fatty acid, and complement C3 and negatively with adiponectin, CEBPα, CEBPβ, and peroxisome proliferator-activated receptor-γ mRNA expression in omental, but not subcutaneous, adipose tissue. Our results suggest that, beyond its neuroendocrine and inflammatory effects, SP could also be involved in targeting adipose tissue and influencing insulin resistance.
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http://dx.doi.org/10.1152/ajpgi.00162.2012DOI Listing
February 2013

Brain activation following peripheral administration of the GLP-1 receptor agonist exendin-4.

Am J Physiol Regul Integr Comp Physiol 2011 Oct 20;301(4):R1011-24. Epub 2011 Jul 20.

Merck-Frosst/Canadian Institutes of Health Research Chair in Obesity and Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada.

The aim of our study was to investigate the anorectic and brain stimulatory effects of various doses of exendin-4 (Ex-4) and to investigate the role of the vagus nerve in Ex-4-induced brain activation. A dose-related increase in c-fos mRNA expression was observed following Ex-4 administration (0.155-15.5 μg/kg). Doses of Ex-4 that caused anorexia without aversive effects (0.155, 0.775 μg/kg) induced c-fos expression in the hypothalamic arcuate and paraventricular (PVH; parvocellular) nuclei as well as in the limbic and brainstem structures. Doses of Ex-4 that caused aversion (1.55, 15.5 μg/kg) stimulated the same regions (in a more intense way) and additionally activated the magnocellular hypothalamic structures (supraoptic nucleus and PVH magnocellular). The brain c-fos pattern induced by Ex-4 showed both similarities and differences with that induced by refeeding. Subdiaphragmatic vagotomy significantly blunted the stimulation of c-fos mRNA expression induced by Ex-4 in the nodose ganglion, the medial part of nucleus of the solitary tract, and the parvocellular division of the PVH. Pretreatment with Ex-9-39 (330 μg/kg ip) impaired the neuronal activation evoked by Ex-4 in all brain regions and in the nodose ganglion. Effects of Ex-4 on hypothalamic-pituitary-adrenal axis activity were not altered by vagotomy. Results of this study demonstrate and relate the anorectic and brain stimulatory effects of aversive and nonaversive doses of Ex-4 and indicate that the activation of specific central regions induced by the peripheral administration of Ex-4 is, at least in part, dependent on the integrity of the vagus nerve.
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http://dx.doi.org/10.1152/ajpregu.00424.2010DOI Listing
October 2011

Motilin stimulates preadipocyte proliferation and differentiation and adipocyte lipid storage.

Am J Physiol Endocrinol Metab 2011 Nov 19;301(5):E758-66. Epub 2011 Jul 19.

Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec, Canada.

Motilin is a circulating gastrointestinal peptide secreted primarily by duodenal mucosal M cells and recognized for its prokinetic effects on gastrointestinal tissues. Little information is available regarding effects on insulin/glucose homeostasis or adipocyte function. Our aim was to evaluate the effects of motilin on adipocyte proliferation, differentiation, lipolysis, and macronutrient uptake in adipocytes. 3T3-L1 cells and primary rat adipocytes were treated acutely and chronically with varying motilin concentrations, and effects were compared with vehicle alone (control), set as 100% for all assays. In preadipocytes, motilin stimulated proliferation ([(3)H]thymidine incorporation) and mitochondrial activity (141 ± 10%, P < 0.001 and 158 ± 10%, respectively, P < 0.001), in a concentration-dependent manner. Chronic supplementation with motilin during differentiation further increased lipogenesis (Oil red O staining 191 ± 27%, P < 0.05) and was associated with an upregulation of PPARγ (148 ± 8%, P < 0.01), C/EBPα (142 ± 17%, P < 0.05), and Cav3 (166 ± 20%, P < 0.05) expression. In mature 3T3-L1 adipocytes motilin increased fatty acid uptake/incorporation (≤ 202 ± 12%; P < 0.01) and glucose uptake (146 ± 9% P < 0.05) and decreased net fatty acid release (maximal -31%, P < 0.05) without influencing total lipolysis (glycerol release). Similar effects were obtained in primary rat adipocytes. Motilin acutely increased expression of PPARγ, CEBPβ, DGAT1, and CD36 while decreasing adiponectin mRNA and secretion. In human adipose tissue, motilin receptor GPR38 correlated with HOMA-IR and GHSR1 (r = 0.876, P < 0.0001). Motilin binding and fatty acid incorporation into adipocytes were inhibited by antagonists MB10 and [D-lys3]-GRP6 and PI 3-kinase inhibitor wortmannin. Taken together, these results suggest that motilin may directly influence adipocyte functions by stimulating energy storage.
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http://dx.doi.org/10.1152/ajpendo.00089.2011DOI Listing
November 2011

Effect of desacyl ghrelin, obestatin and related peptides on triglyceride storage, metabolism and GHSR signaling in 3T3-L1 adipocytes.

J Cell Biochem 2011 Feb;112(2):704-14

Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada.

Acyl-ghrelin (AG), desacyl-ghrelin (DAG) and obestatin are all derived from the same gene transcript; however their plasma levels do not necessarily change in parallel. The influence of these peptides towards the development of obesity and their direct effects on adipocyte physiology has not been thoroughly investigated. This study was designed to evaluate the direct effects of peptides of the ghrelin family on preadipocyte proliferation, differentiation and adipocyte lipid and glucose metabolism in 3T3-L1 cells. 3T3 cells were treated with physiological peptide concentrations for 1 h to 9 days, and the relevant assays measured. In preadipocytes, AG, GHRP-6 and DAG stimulated proliferation, measured as (3)H-thymidine incorporation (up to 200%, P < 0.05), while all peptides stimulated differentiation (up to 300%, P < 0.01) as compared to standard differentiation conditions. In adipocytes, FA uptake was increased in a concentration-dependent manner especially with obestatin (three- to fourfold, P < 0.001) and DAG (three- to fivefold, P < 0.001). By contrast, glucose transport was unchanged. DAG and obestatin significantly decreased lipolysis measured as non-esterified fatty acid and glycerol release by 50%, P < 0.05-0.01 and 51%, P < 0.01, respectively. Interestingly, DAG stimulation of FA uptake was blocked with GHSR1 antagonist (D-lys(3))-GHRP-6 (P < 0.05), phospholipase C inhibitor U73122 and phosphatidylinositol-3-kinase inhibitor wortmannin (P < 0.001). Finally, in omental but not subcutaneous human adipose tissue, GHSR1 correlated with BMI (r = 0.549, P < 0.05) and insulin (r = 0.681, P < 0.01). Taken together, these results suggest that ghrelin-related peptides may directly affect adipose tissue metabolism.
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http://dx.doi.org/10.1002/jcb.22983DOI Listing
February 2011

Fiber intake predicts ghrelin levels in overweight and obese postmenopausal women.

Eur J Endocrinol 2009 Jul 15;161(1):65-72. Epub 2009 Apr 15.

Département de, Nutrition et de Médecine, Université de Montréal, Montréal, Québec, Canada.

Background: Ghrelin levels are decreased upon food intake, but the impact of specific diet-derived macronutrients on its regulation remains unclear. In addition, because of ghrelin's association with body weight regulation, it is important to understand the mechanisms regulating its levels in obese individuals.

Objective: To examine the effect of specific macronutrients on ghrelin levels in overweight and obese postmenopausal women.

Methods: Thirty-five subjects underwent a euglycemic/hyperinsulinemic clamp (EHC) to examine glucose disposal and total ghrelin (TotG) and acylated ghrelin (AG) levels. Macronutrient intake was evaluated with a 3-day food questionnaire.

Results: Under fasting conditions, positive associations were observed between fiber intake and TotG and AG levels. Fasting AG also correlated positively with the intake of total energy, as well as monounsaturated and polyunsaturated lipids. Importantly, fiber consumption explained up to 26 and 23% of the variation in TotG and AG respectively. During the EHC, TotG levels were significantly reduced at all times, while AG was decreased at 60 min only. TotG area under the curve (AUC) values were positively associated with fiber and polyunsaturated lipid intake, while AG AUC values correlated positively with fiber, total energy, carbohydrate, and lipid intake. Interestingly, fiber intake explained up to 21% of the variation in TotG AUC, while total energy intake predicted up to 21% of the variation in the AG AUC.

Conclusion: The present study suggests that fiber intake is an important regulator of ghrelin levels both in fasting and in hyperinsulinemic conditions. Overall, these results reinforce the importance of the intimate association between eating habits and gastrointestinal hormonal regulation.
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http://dx.doi.org/10.1530/EJE-09-0018DOI Listing
July 2009

Change in plasma acylation stimulating protein during euglycaemic-hyperinsulinaemic clamp in overweight and obese postmenopausal women: a MONET study.

Clin Endocrinol (Oxf) 2009 Apr 13;70(4):539-46. Epub 2008 Aug 13.

Département de Nutrition, Université de Montréal, Montréal, Québec, Canada.

Objective: Acylation-stimulating protein (ASP) has been shown to positively stimulate fatty acid esterification and glucose uptake in adipocytes. In vitro studies demonstrate that insulin stimulates ASP secretion from adipocytes. Individuals with obesity and/or metabolic disturbances (insulin resistance and type 2 diabetes) have increased plasma ASP.

Design: The present study was designed to evaluate whether ASP levels are influenced by the metabolic profiles of overweight and obese postmenopausal women during a euglycaemic/hyperinsulinaemic clamp (EHC). Patients The study population consisted of 76 overweight and obese sedentary postmenopausal women.

Measurements: We evaluated insulin sensitivity, plasma ASP levels, body composition including visceral adipose tissue area, blood lipid profiles, liver enzymes, peak aerobic capacity, resting metabolic rate (RMR) and total energy expenditure (TEE).

Results: We observed wide interindividual variations of ASP levels during the EHC. Therefore, subjects were divided into three groups based on ASP changes. Negative ASP Responders (NAR; n = 24) showed a -20% or greater decrease in ASP levels while Positive ASP Responders (PAR; n = 42) displayed ASP fluctuations superior to +20%. Ten subjects had little or no ASP change and were considered as Zero ASP responders (ZAR). PAR women displayed a worse metabolic profile than NAR women, including higher BMI, visceral adipose tissue, fasting insulin levels, lean body mass, and alanine aminotransferase (ALT), a marker of impaired liver function. After adjustment for BMI, only ALT remained significantly different, while lean body mass (P = 0.08) and visceral adipose tissue (P = 0.07) remained marginally higher. Correlation analysis of all subjects demonstrated that fasting ASP levels correlated positively with albumin and VO(2 peak) and this association remained significant after adjustments for the effect of BMI. In addition, the percentage maximal change in ASP levels during the EHC was positively associated with BMI, lean body mass, visceral adipose tissue, fasting insulin, HOMA, TEE, RMR, ALT and AST.

Conclusion: Overall these results suggest that an elevated ASP response during the EHC is associated with metabolic disturbances in overweight and obese postmenopausal women.
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http://dx.doi.org/10.1111/j.1365-2265.2008.03353.xDOI Listing
April 2009

Preproghrelin-derived peptide, obestatin, fails to influence food intake in lean or obese rodents.

Obesity (Silver Spring) 2007 Nov;15(11):2643-52

Center for Ulcer Research and Education (CURE): Digestive Diseases Research Center, and Center for Neurovisceral Sciences and Women's Health, Department of Medicine, Division of Digestive Diseases, University of California-Los Angeles, USA.

Objectives: Obestatin has been initially characterized as a new peptide derived from the ghrelin precursor, which suppresses food intake and inhibits the orexigenic and prokinetic actions of ghrelin when injected peripherally or centrally in lean mice. However, reproducing these data remains controversial. Reasons for the disparity may be the use of different doses, routes, and animal models. We aimed to investigate the effects of peripheral and intracisternal (IC) injection of obestatin on feeding, gastric motility, and blood glucose in rats as well as in diet-induced obese (DIO) mice.

Research Methods And Procedures: Food intake and gastric emptying of a semi-liquid caloric meal were measured after intraperitoneal (IP) injection of obestatin in rats and DIO mice. Gastric phasic motility and blood glucose were monitored in urethane-anesthetized rats after IC or intravenous (IV) injection of obestatin.

Results: Obestatin injected intraperitoneally at doses ranging from 0.1 to 3 mg/kg influenced neither acute food intake nor gastric emptying in rats. Obestatin injected intravenously at 0.3 or 3 mg/kg and IC at 7.5 or 30 microg/rat modified neither fasted gastric phasic motility nor blood glucose levels, while ghrelin (30 microg/kg, IV) increased and vagotomy suppressed gastric motility, and an oligosomatostatin analog (3 microg/rat, IC) decreased blood glucose. Obestatin, injected intraperitoneally (0.3 mg/kg) in DIO mice, did not alter feeding response to a fast, while urocortin 1 (10 microg/kg, IP) induced a 73.3% inhibition at 2 hours.

Discussion: Our data demonstrate that peripheral administration of obestatin did not modify food intake in rats or obese mice or gastric motor function in rats.
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http://dx.doi.org/10.1038/oby.2007.316DOI Listing
November 2007

Relationship between insulin sensitivity and the triglyceride-HDL-C ratio in overweight and obese postmenopausal women: a MONET study.

Appl Physiol Nutr Metab 2007 Dec;32(6):1089-96

Department of Kinanthropology, Université du Québec à Montréal, Montreal, QC H2X 3R9, Canada.

The objective of this cross-sectional study was to examine the relationship between the triglyceride-HDL-cholesterol ratio (TG:HDL-C) and insulin sensitivity in overweight and obese sedentary postmenopausal women. The study population consisted of 131 non-diabetic overweight and obese sedentary postmenopausal women (age; 57.7+/-5.0 y; body mass index (BMI), 32.2+/-4.3 kg/m2). Subjects were characterized by dividing the entire cohort into tertiles based on the TG:HDL-C (T1<0.86 vs. T2=0.86 to 1.35 vs. T3>1.35, respectively). We measured (i) insulin sensitivity (using the hyperinsulinenic-euglycemic clamp and homeostasis model assessment (HOMA)), (ii) body composition (using dual-energy X-ray absorptiometry), (iii) visceral fat (using computed tomography), (iv) plasma lipids, C-reactive protein, 2 h glucose concentration during an oral glucose tolerance test (2 h glucose), as well as fasting glucose and insulin, (v) peak oxygen consumption, and (vi) lower-body muscle strength (using weight training equipment). Significant correlations were observed between the TG:HDL-C and the hyperinsulinemic-euglycemic clamp (r=-0.45; p<0.0001), as well as with HOMA (r=0.42; p<0.0001). Moreover, the TG:HDL-C significantly correlated with lean body mass, visceral fat, 2 h glucose, C-reactive protein, and muscle strength. Stepwise regression analysis showed that the TG:HDL-C explained 16.4% of the variation in glucose disposal in our cohort, which accounted for the greatest source of unique variance. Other independent predictors of glucose disposal were 2 h glucose (10.1%), C-reactive protein (CRP; 7.6%), and peak oxygen consumption (5.8%), collectively (including the TG:HDL-C) explaining 39.9% of the unique variance. In addition, the TG:HDL-C was the second predictor for HOMA, accounting for 11.7% of the variation. High levels of insulin sensitivity were associated with low levels of the TG:HDL-C. In addition, the TG:HDL-C was a predictor for glucose disposal rates and HOMA values in our cohort of overweight and obese postmenopausal women.
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http://dx.doi.org/10.1139/H07-095DOI Listing
December 2007

Association of acylated ghrelin profiles with chronic inflammatory markers in overweight and obese postmenopausal women: a MONET study.

Eur J Endocrinol 2007 Oct;157(4):419-26

Département de Nutrition, Université de Montréal, Montréal, Québec, Canada, H3T 1A8.

Objective: Recent reports have suggested that the existence of associations between hormonal dysregulation and chronic upregulation of inflammatory markers, which may cause obesity-related disturbances. Thus, we examined whether acylated ghrelin (AcylG) and total ghrelin (TotG) levels could be associated with the following inflammatory markers: C-reactive protein (CRP), tumor necrosis factor alpha (TNF-alpha), and soluble TNF receptor 1 (sTNF-R1).

Design: Cross-sectional study consisting of 50 overweight and obese postmenopausal women.

Methods: AcylG and TotG levels were assessed at 0, 60, 160, 170, and 180 min of the euglycemic/hyperinsulinemic clamp (EHC). We evaluated insulin sensitivity, body composition, and blood lipid profiles as well as fasting concentrations of CRP, TNF-alpha, and sTNF-R1.

Results: In fasting conditions, sTNF-R1 was negatively correlated with AcylG (r = -0.48, P < 0.001) levels. In addition, AcylG/TotG was associated negatively with sTNF-R1 (r = -0.44, P = 0.002) and positively with TNF-alpha (r = 0.38, P = 0.009) values. During the EHC, TotG (at all time points) and AcylG (at 60 and 160 min) values were significantly decreased from fasting concentrations. AcylG maximal reduction and area under the curve (AUC) values were correlated to sTNF-R1 (r = -0.35, P = 0.02 and r = -0.34, P = 0.02, respectively). Meanwhile, the AcylG/TotG AUC ratio was associated negatively with sTNF-R1 (r = -0.29, P < 0.05) and positively with TNF-alpha (r = 0.36, P = 0.02). Following adjustments for total adiposity, sTNF-R1 remained correlated with fasting and maximal reduction AcylG values. Similarly, AcylG/TotG ratios remained significantly correlated with sTNF-R1 and TNF-alpha. Importantly, 23% of the variation in sTNF-R1 was independently predicted by fasting AcylG.

Conclusion: These results are the first to suggest that both fasting and EHC-induced AcylG profiles are correlated with fasting values of sTNF-R1, a component of the TNF-alpha system. Thus, AcylG may act, at least in part, as one mediator of chronic inflammatory activity in human obesity.
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http://dx.doi.org/10.1530/EJE-07-0038DOI Listing
October 2007

Association of insulin sensitivity and muscle strength in overweight and obese sedentary postmenopausal women.

Appl Physiol Nutr Metab 2007 Apr;32(2):297-301

Department of Kinanthropology, Université du Québec à Montréal, 1205 St-Denis, Montreal, QC H2X 3R9, Canada.

The objective of this study was to examine the relationship between insulin sensitivity and lower body muscle strength in overweight and obese sedentary postmenopausal women. The design of the study was cross-sectional. The study population consisted of 82 non-diabetic overweight and obese sedentary postmenopausal women (age: 58.2 +/- 5.1 y; body mass index (BMI): 32.4 +/- 4.6 kg.m-2). Subjects were classified by dividing the entire cohort into quartiles based on relative insulin sensitivity expressed per kilograms of lean body mass (LBM) (Q1, < 10.3, vs. Q2, 10.3-12.4, vs. Q3, 12.5-14.0, vs. Q4, >14.0 mg.min-1.kg LBM-1). We measured insulin sensitivity (using the hyperinsulinemic-euglycemic clamp technique), body composition (using dual-energy X-ray absorptiometry), visceral fat and muscle attenuation (using computed tomography), and a lower-body muscle strength index expressed as weight lifted in kilograms per kilogram of LBM (kg.kg LBM-1) (using weight-training equipment). A positive and significant relationship was observed between insulin sensitivity and the muscle strength index (r = 0.37; p < 0.001). Moreover, a moderate but significant correlation was observed between the muscle strength index and muscle attenuation (r = 0.22; p < 0.05). Finally, the muscle strength index was significantly higher in the Q4 group compared with the Q2 and Q1 groups, respectively (3.78 +/- 1.13 vs. 2.99 +/- 0.77 and 2.93 +/- 0.91 kg.kg LBM-1; p < 0.05). Insulin sensitivity is positively associated with lower-body muscle strength in overweight and obese sedentary postmenopausal women.
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http://dx.doi.org/10.1139/H07-002DOI Listing
April 2007