Publications by authors named "Joram D Mul"

35 Publications

How the COVID-19 pandemic highlights the necessity of animal research.

November 2020

How the COVID-19 pandemic highlights the necessity of animal research.

Curr Biol 2020 09 10;30(18):R1014-R1018. Epub 2020 Aug 10.

Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands. Electronic address:

Recently, a petition was offered to the European Commission calling for an immediate ban on animal testing. Although a Europe-wide moratorium on the use of animals in science is not yet possible, there has been a push by the non-scientific community and politicians for a rapid transition to animal-free innovations. Although there are benefits for both animal welfare and researchers, advances on alternative methods have not progressed enough to be able to replace animal research in the foreseeable future. This trend has led first and foremost to a substantial increase in the administrative burden and hurdles required to make timely advances in research and treatments for human and animal diseases. The current COVID-19 pandemic clearly highlights how much we actually rely on animal research. COVID-19 affects several organs and systems, and the various animal-free alternatives currently available do not come close to this complexity. In this Essay, we therefore argue that the use of animals is essential for the advancement of human and veterinary health.
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http://dx.doi.org/10.1016/j.cub.2020.08.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416712PMC
September 2020

Effects of Neuropeptide Y administration into the lateral hypothalamus on intake of free-choice high-fat high-sucrose diet components of the male Wistar rat.

Nutr Neurosci 2020 Jul 13:1-10. Epub 2020 Jul 13.

Department of Endocrinology and Metabolism & Laboratory of Endocrinology, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Neuropeptide Y (NPY) signaling in the brain plays an important role in energy regulation, and is altered during diet-induced obesity. Yet, NPY function during the consumption of specific diet components remains to be fully determined. We have previously demonstrated that consumption of a saturated fat component (free-choice high-fat; fcHF), a sucrose solution (high-sugar; fcHS), or both (fcHFHS) combined with a standard diet (chow and water) has diverse effects on expression in the arcuate nucleus and the sensitivity to intraventricular NPY administration. Arcuate NPY neurons project to the lateral hypothalamus (LHA), and NPY administration in the LHA potently promotes chow intake in rats on a standard diet. However, it is currently unclear if short-term consumption of a palatable free-choice diet alters NPY function in the LHA. Therefore, we assessed the effects of intra-LHA NPY administration on intake in rats following one-week consumption of a fcHF, fcHS, or fcHFHS diet. Male Wistar rats consumed a fcHF, fcHS, fcHFHS, or control (CHOW) diet for one week before NPY (0.3 μg / 0.3 μL) or phosphate-buffered saline (0.3 μL) was administered into the LHA. Intake was measured 2h later. fcHFHS-fed rats were divided into high-fat (fcHFHS-hf) and low-fat (fcHFHS-lf) groups based on differences in basal fat intake. Intra-LHA NPY administration increased chow intake in fcHFHS- (irrespective of basal fat intake), fcHF- and CHOW-fed rats. Intra-LHA NPY infusion increased fat intake in fcHF-, fcHFHS-hf, but not fcHFHS-lf, rats. Intra-LHA NPY infusion did not increase caloric intake in fcHS-fed rats. Our data demonstrate that the effects of intra-LHA NPY on caloric intake differ depending on the consumption of a fat or sugar component, or both, in a free-choice diet. Our data also indicate that baseline preference for the fat diet component modulates the effects of intra-LHA NPY in fcHFHS-fed rats.
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http://dx.doi.org/10.1080/1028415X.2020.1788774DOI Listing
July 2020

Maternal and paternal exercise regulate offspring metabolic health and beta cell phenotype.

BMJ Open Diabetes Res Care 2020 02;8(1)

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts, USA

Objective: Poor maternal and paternal environments increase the risk for obesity and diabetes in offspring, whereas maternal and paternal exercise in mice can improve offspring metabolic health. We determined the effects of combined maternal and paternal exercise on offspring health and the effects of parental exercise on offspring pancreas phenotype, a major tissue regulating glucose homeostasis.

Research Design And Methods: Breeders were high fat fed and housed±running wheels before breeding (males) and before and during gestation (females). Offspring groups were: both parents sedentary (Sed); maternal exercise only (Mat Ex); paternal exercise only (Pat Ex); and maternal+paternal exercise (Mat+Pat Ex). Offspring were sedentary, chow fed, and studied at weaning, 12, 20 and 52 weeks.

Results: While there was no effect of parental exercise on glucose tolerance at younger ages, at 52 weeks, offspring of Mat Ex, Pat Ex and Mat+Pat Ex displayed lower glycemia and improved glucose tolerance. The greatest effects were in offspring from parents that both exercised (Mat+Pat Ex). Offspring from Mat Ex, Pat Ex, and Mat+Pat Ex had decreased beta cell size, whereas islet size and beta cell mass only decreased in Mat+Pat Ex offspring.

Conclusions: Maternal and paternal exercise have additive effects to improve glucose tolerance in offspring as they age, accompanied by changes in the offspring endocrine pancreas. These findings have important implications for the prevention and treatment of type 2 diabetes.
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http://dx.doi.org/10.1136/bmjdrc-2019-000890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050345PMC
February 2020

Sex-dependent effects of MC4R genotype on HPA axis tone: implications for stress-associated cardiometabolic disease.

Stress 2019 09 11;22(5):571-580. Epub 2019 Jun 11.

a Department of Neurobiology, Physiology and Behavior, University of California , Davis , CA , USA.

The melanocortin-4 receptor (MC4R) facilitates hypothalamic-pituitary-adrenocortical (HPA) axis responses to acute stress in male rodents and is a well known to regulator of energy balance. Mutations in the MC4R is the most common monogenic cause of obesity in humans and has been associated with sex-specific effects, but whether stress regulation by the MC4R is sex-dependent, and whether the MC4R facilitates HPA responses to chronic stress, is unknown. We hypothesized that MC4R-signaling contributes to HPA axis dysregulation and metabolic pathophysiology following chronic stress exposure. We measured changes in energy balance, HPA axis tone, and vascular remodeling during chronic variable stress (CVS) in male and female rats with MC4R loss-of-function. Rats were placed into three groups ( = 9-18/genotype/sex) and half of each group was subjected to CVS for 30 days or were non-stressed littermate controls. All rats underwent an acute restraint stress challenge on Day 30. Rats were euthanized on Day 31, adrenals collected for weight, and descending aortas fixed for morphological indices of vascular pathophysiology. We observed a marked interaction between genotype and sex for basal HPA axis tone and acute stress responsivity. MC4R loss-of-function blunted both endpoints in males but exaggerated them in females. Contrary to our hypothesis, genotype had no effect on either HPA axis responses or metabolic responses to chronic stress. Heightened stress reactivity of females with MC4R mutations suggests a possible mechanism for the sex-dependent effects associated with this mutation in humans and highlights how stress may differentially regulate metabolism in males and females. The hypothalamic melanocortin system is an important regulator of energy balance and stress responses. Here, we report a sex-difference in the stress reactivity of rats with a mutation in this system. Our findings highlight how stress may regulate metabolism differently in males and females and may provide insight into sex-differences associated with this mutation in humans.
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http://dx.doi.org/10.1080/10253890.2019.1610742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690797PMC
September 2019

TGF-β2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism.

Nat Metab 2019 02 11;1(2):291-303. Epub 2019 Feb 11.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.

Exercise improves health and well-being across diverse organ systems, and elucidating mechanisms underlying the beneficial effects of exercise can lead to new therapies. Here, we show that transforming growth factor-β2 (TGF-β2) is secreted from adipose tissue in response to exercise and improves glucose tolerance in mice. We identify TGF-β2 as an exercise-induced adipokine in a gene expression analysis of human subcutaneous adipose tissue biopsies after exercise training. In mice, exercise training increases TGF-β2 in scWAT, serum, and its secretion from fat explants. Transplanting scWAT from exercise-trained wild type mice, but not from adipose tissue-specific Tgfb2-/- mice, into sedentary mice improves glucose tolerance. TGF-β2 treatment reverses the detrimental metabolic effects of high fat feeding in mice. Lactate, a metabolite released from muscle during exercise, stimulates TGF-β2 expression in human adipocytes. Administration of the lactate-lowering agent dichloroacetate during exercise training in mice decreases circulating TGF-β2 levels and reduces exercise-stimulated improvements in glucose tolerance. Thus, exercise training improves systemic metabolism through inter-organ communication with fat via a lactate-TGF-β2-signaling cycle.
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http://dx.doi.org/10.1038/s42255-018-0030-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481955PMC
February 2019

Stressing the importance of choice: Validity of a preclinical free-choice high-caloric diet paradigm to model behavioural, physiological and molecular adaptations during human diet-induced obesity and metabolic dysfunction.

J Neuroendocrinol 2019 05 24;31(5):e12718. Epub 2019 Apr 24.

Department of Endocrinology and Metabolism, Laboratory of Endocrinology, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Humans have engineered a dietary environment that has driven the global prevalence of obesity and several other chronic metabolic diseases to pandemic levels. To prevent or treat obesity and associated comorbidities, it is crucial that we understand how our dietary environment, especially in combination with a sedentary lifestyle and/or daily-life stress, can dysregulate energy balance and promote the development of an obese state. Substantial mechanistic insight into the maladaptive adaptations underlying caloric overconsumption and excessive weight gain has been gained by analysing brains from rodents that were eating prefabricated nutritionally-complete pellets of high-fat diet (HFD). Although long-term consumption of HFDs induces chronic metabolic diseases, including obesity, they do not model several important characteristics of the modern-day human diet. For example, prefabricated HFDs ignore the (effects of) caloric consumption from a fluid source, do not appear to model the complex interplay in humans between stress and preference for palatable foods, and, importantly, lack any aspect of choice. Therefore, our laboratory uses an obesogenic free-choice high-fat high-sucrose (fc-HFHS) diet paradigm that provides rodents with the opportunity to choose from several diet components, varying in palatability, fluidity, texture, form and nutritive content. Here, we review recent advances in our understanding how the fc-HFHS diet disrupts peripheral metabolic processes and produces adaptations in brain circuitries that govern homeostatic and hedonic components of energy balance. Current insight suggests that the fc-HFHS diet has good construct and face validity to model human diet-induced chronic metabolic diseases, including obesity, because it combines the effects of food palatability and energy density with the stimulating effects of variety and choice. We also highlight how behavioural, physiological and molecular adaptations might differ from those induced by prefabricated HFDs that lack an element of choice. Finally, the advantages and disadvantages of using the fc-HFHS diet for preclinical studies are discussed.
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http://dx.doi.org/10.1111/jne.12718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593820PMC
May 2019

Afferent neuropeptide Y projections to the ventral tegmental area in normal-weight male Wistar rats.

J Comp Neurol 2019 11 18;527(16):2659-2674. Epub 2019 Apr 18.

Department of Endocrinology and Metabolism & Laboratory of Endocrinology, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

The hypothalamic neuropeptide Y (NPY) circuitry is a key regulator of feeding behavior. NPY also acts in the mesolimbic dopaminergic circuitry, where it can increase motivational aspects of feeding behavior through effects on dopamine output in the nucleus accumbens (NAc) and on neurotransmission in the ventral tegmental area (VTA). Endogenous NPY in the NAc originates from local interneurons and afferent projections from the hypothalamic arcuate nucleus (Arc). However, the origin of endogenous NPY in the VTA is unknown. We determined, in normal-weight male Wistar rats, if the source of VTA NPY is local, and/or whether it is derived from VTA-projecting neurons. Immunocytochemistry, in situ hybridization and RT-qPCR were utilized, when appropriate in combination with colchicine treatment or 24 hr fasting, to assess NPY/Npy expression locally in the VTA. Retrograde tracing using cholera toxin beta (CTB) in the VTA, fluorescent immunocytochemistry and confocal microscopy were used to determine NPY-immunoreactive afferents to the VTA. NPY in the VTA was observed in fibers, but not following colchicine pretreatment. No NPY- or Npy-expressing cell bodies were observed in the VTA. Fasting for 24 hr, which increased Npy expression in the Arc, failed to induce Npy expression in the VTA. Double-labeling with CTB and NPY was observed in the Arc and in the ventrolateral medulla. Thus, VTA NPY originates from the hypothalamic Arc and the ventrolateral medulla of the brainstem in normal-weight male Wistar rats. These afferent connections link hypothalamic and brainstem processing of physiologic state to VTA-driven motivational behavior.
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http://dx.doi.org/10.1002/cne.24698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767444PMC
November 2019

Voluntary wheel running promotes resilience to chronic social defeat stress in mice: a role for nucleus accumbens ΔFosB.

Neuropsychopharmacology 2018 08 24;43(9):1934-1942. Epub 2018 May 24.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, 02215, USA.

Elucidating mechanisms by which physical exercise promotes resilience, the brain's ability to cope with prolonged stress exposure while maintaining normal psychological functioning, is a major research challenge given the high prevalence of stress-related mental disorders, including major depressive disorder. Chronic voluntary wheel running (VWR), a rodent model that mimics aspects of human physical exercise, induces the transcription factor ΔFosB in the nucleus accumbens (NAc), a key reward-related brain area. ΔFosB expression in NAc modulates stress susceptibility. Here, we explored whether VWR induction of NAc ΔFosB promotes resilience to chronic social defeat stress (CSDS). Male young-adult C57BL/6J mice were single housed for up to 21 d with or without running wheels and then subjected to 10 d of CSDS. Stress-exposed sedentary mice developed a depressive-like state, characterized by anhedonia and social avoidance, whereas stress-exposed mice that had been wheel running showed resilience. Functional inhibition of NAc ΔFosB during VWR, by viral-mediated overexpression of a transcriptionally inactive JunD mutant, reinstated susceptibility to CSDS. Within the NAc, VWR induction of ΔFosB was CREB-dependent, associated with altered dendritic morphology, and medium spiny neuron (MSN) subtype specific in the NAc core and shell subregions. Finally, when mice performed VWR following the onset of CSDS-induced social avoidance, VWR normalized such behavior. These data indicate that VWR promoted resilience to CSDS, and suggest that sustained induction of ΔFosB in the NAc underlies, at least in part, the stress resilience mediated by VWR. These findings provide a potential framework for the development of treatments for stress-associated mental illnesses based on physical exercise.
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http://dx.doi.org/10.1038/s41386-018-0103-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046059PMC
August 2018

Voluntary exercise and depression-like behavior in rodents: are we running in the right direction?

Authors:
Joram D Mul

J Mol Endocrinol 2018 04 12;60(3):R77-R95. Epub 2018 Jan 12.

Department of Endocrinology and MetabolismAcademic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

Acute or chronic exposure to stress can increase the risk to develop major depressive disorder, a severe, recurrent and common psychiatric condition. Depression places an enormous social and financial burden on modern society. Although many depressed patients are treated with antidepressants, their efficacy is only modest, underscoring the necessity to develop clinically effective pharmaceutical or behavioral treatments. Exercise training produces beneficial effects on stress-related mental disorders, indicative of clinical potential. The pro-resilient and antidepressant effects of exercise training have been documented for several decades. Nonetheless, the underlying molecular mechanisms and the brain circuitries involved remain poorly understood. Preclinical investigations using voluntary wheel running, a frequently used rodent model that mimics aspects of human exercise training, have started to shed light on the molecular adaptations, signaling pathways and brain nuclei underlying the beneficial effects of exercise training on stress-related behavior. In this review, I highlight several neurotransmitter systems that are putative mediators of the beneficial effects of exercise training on mental health, and review recent rodent studies that utilized voluntary wheel running to promote our understanding of exercise training-induced central adaptations. Advancements in our mechanistic understanding of how exercise training induces beneficial neuronal adaptations will provide a framework for the development of new strategies to treat stress-associated mental illnesses.
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http://dx.doi.org/10.1530/JME-17-0165DOI Listing
April 2018

Glucose-Sensing in the Reward System.

Front Neurosci 2017 19;11:716. Epub 2017 Dec 19.

Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.

Glucose-sensing neurons are neurons that alter their activity in response to changes in extracellular glucose. These neurons, which are an important mechanism the brain uses to monitor changes in glycaemia, are present in the hypothalamus, where they have been thoroughly investigated. Recently, glucose-sensing neurons have also been identified in brain nuclei which are part of the reward system. However, little is known about the molecular mechanisms by which they function, and their role in the reward system. We therefore aim to provide an overview of molecular mechanisms that have been studied in the hypothalamic glucose-sensing neurons, and investigate which of these transporters, enzymes and channels are present in the reward system. Furthermore, we speculate about the role of glucose-sensing neurons in the reward system.
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http://dx.doi.org/10.3389/fnins.2017.00716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742113PMC
December 2017

The effects of overnight nutrient intake on hypothalamic inflammation in a free-choice diet-induced obesity rat model.

Appetite 2018 Jan 5;120:527-535. Epub 2017 Oct 5.

Department of Endocrinology and Metabolism, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, The Netherlands; Laboratory of Endocrinology, Department of Clinical Chemistry, AMC, UvA, Amsterdam, The Netherlands; Metabolism and Reward Group, Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands. Electronic address:

Consumption of fat and sugar induces hyperphagia and increases the prevalence of obesity and diabetes type 2. Low-grade inflammation in the hypothalamus, a key brain area involved in the regulation of energy homeostasis is shown to blunt signals of satiety after long term high fat diet. The fact that this mechanism can be activated after a few days of hyperphagia before apparent obesity is present led to our hypothesis that hypothalamic inflammation is induced with fat and sugar consumption. Here, we used a free-choice high-fat high-sugar (fcHFHS) diet-induced obesity model and tested the effects of differential overnight nutrient intake during the final experimental night on markers of hypothalamic inflammation. Male Wistar rats were fed a control diet or fcHFHS diet for one week, and assigned to three different feeding conditions during the final experimental night: 1) fcHFHS-fed, 2) fed a controlled amount of chow diet, or 3) fasted. RT-qPCR and Western blot were utilized to measure hypothalamic gene and protein expression, of cytokines and intermediates of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Lastly, we investigated the effects of acute fat intake on markers of hypothalamic inflammation in fat-naïve rats. fcHFHS-fed rats consumed more calories, increased adipose tissue, and showed elevated expression of hypothalamic inflammation markers (increased phosphorylation of NF-κB protein, Nfkbia and Il6 gene expression) compared to chow-fed rats. These effects were evident in rats consuming relative high amounts of fat. Removal of the fat and sugar, or fasting, during the final experimental night ameliorated hypothalamic inflammation. Finally, a positive correlation was observed between overnight acute fat consumption and hypothalamic NF-κB phosphorylation in fat-naïve rats. Our data indicate that one week of fcHFHS diet, and especially the fat component, promotes hypothalamic inflammation, and removal of the fat and sugar component reverses these detrimental effects.
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http://dx.doi.org/10.1016/j.appet.2017.10.006DOI Listing
January 2018

Validity Assessment of 5 Day Repeated Forced-Swim Stress to Model Human Depression in Young-Adult C57BL/6J and BALB/cJ Mice.

eNeuro 2016 Nov-Dec;3(6). Epub 2016 Dec 29.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215; Department of Medicine, Brigham, and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215.

The development of animal models with construct, face, and predictive validity to accurately model human depression has been a major challenge. One proposed rodent model is the 5 d repeated forced swim stress (5d-RFSS) paradigm, which progressively increases floating during individual swim sessions. The onset and persistence of this floating behavior has been anthropomorphically characterized as a measure of depression. This interpretation has been under debate because a progressive increase in floating over time may reflect an adaptive learned behavioral response promoting survival, and not depression (Molendijk and de Kloet, 2015). To assess construct and face validity, we applied 5d-RFSS to C57BL/6J and BALB/cJ mice, two mouse strains commonly used in neuropsychiatric research, and measured a combination of emotional, homeostatic, and psychomotor symptoms indicative of a depressive-like state. We also compared the efficacy of 5d-RFSS and chronic social defeat stress (CSDS), a validated depression model, to induce a depressive-like state in C57BL/6J mice. In both strains, 5d-RFSS progressively increased floating behavior that persisted for at least 4 weeks. 5d-RFSS did not alter sucrose preference, body weight, appetite, locomotor activity, anxiety-like behavior, or immobility behavior during a tail-suspension test compared with nonstressed controls. In contrast, CSDS altered several of these parameters, suggesting a depressive-like state. Finally, predictive validity was assessed using voluntary wheel running (VWR), a known antidepressant intervention. Four weeks of VWR after 5d-RFSS normalized floating behavior toward nonstressed levels. These observations suggest that 5d-RFSS has no construct or face validity but might have predictive validity to model human depression.
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http://dx.doi.org/10.1523/ENEURO.0201-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5197406PMC
October 2017

Maternal high-calorie diet is associated with altered hepatic microRNA expression and impaired metabolic health in offspring at weaning age.

Endocrine 2016 Oct 22;54(1):70-80. Epub 2016 Apr 22.

Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Dongcheng District, Beijing, 100730, China.

High-calorie diet (HCD) feeding in mice predisposes offspring for impaired glucose homeostasis and obesity. However, the mechanisms underlying these detrimental effects of maternal nutrition, especially during early life of offspring, are incompletely understood. MicroRNAs (miRNAs) are small non-coding RNAs that can regulate target gene expression. Here we hypothesized that impaired metabolic health in offspring from HCD-fed dams at weaning is associated with dysregulated expression of hepatic miRNAs. Dams were fed a chow diet (CD; 11.4 % kcal fat, 62.8 % from carbohydrate, 25.8 % from protein) or HCD (58 % kcal from fat; 25.6 % from carbohydrate, 16.4 % from protein) during gestation and lactation, and metabolic health was assessed in male offspring at weaning. Hepatic levels of miRNAs and target genes were investigated in offspring from CD- or HCD-fed dams using gene and protein expression. Maternal HCD feeding impaired metabolic health in offspring compared to offspring from CD-fed dams. Microarray analysis indicated that expressions of miR-615-5p, miR-3079-5p, miR-124*, and miR-101b* were downregulated, whereas miR-143* was upregulated, in livers from offspring from HCD-fed dams. Our functional enrichment analysis indicated that the target genes of these differentially expressed miRNAs, including tumor necrosis factor-α (TNF-α) and mitogen-activated protein kinase 1 (MAPK1), were mapped to inflammatory pathways. Finally, we verified that both mRNA and protein levels of the pro-inflammatory modulators TNF-α and MAPK1 were significantly increased in livers of offspring from HCD-fed dams at weaning. Maternal HCD feeding predisposes offspring to a higher body weight and impaired glucose metabolism at weaning. To the best of knowledge, our study is the first to show that maternal HCD consumption impairs metabolic health, modulates hepatic miRNA expression, and increases markers of hepatic inflammation in offspring as early as at weaning age.
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http://dx.doi.org/10.1007/s12020-016-0959-9DOI Listing
October 2016

Contraction stimulates muscle glucose uptake independent of atypical PKC.

Physiol Rep 2015 Nov;3(11)

Harvard Medical School, Joslin Diabetes Center, Boston, Massachusetts

Exercise increases skeletal muscle glucose uptake, but the underlying mechanisms are only partially understood. The atypical protein kinase C (PKC) isoforms λ and ζ (PKC-λ/ζ) have been shown to be necessary for insulin-, AICAR-, and metformin-stimulated glucose uptake in skeletal muscle, but not for treadmill exercise-stimulated muscle glucose uptake. To investigate if PKC-λ/ζ activity is required for contraction-stimulated muscle glucose uptake, we used mice with tibialis anterior muscle-specific overexpression of an empty vector (WT), wild-type PKC-ζ (PKC-ζ(WT)), or an enzymatically inactive T410A-PKC-ζ mutant (PKC-ζ(T410A)). We also studied skeletal muscle-specific PKC-λ knockout (MλKO) mice. Basal glucose uptake was similar between WT, PKC-ζ(WT), and PKC-ζ(T410A) tibialis anterior muscles. In contrast, in situ contraction-stimulated glucose uptake was increased in PKC-ζ(T410A) tibialis anterior muscles compared to WT or PKC-ζ(WT) tibialis anterior muscles. Furthermore, in vitro contraction-stimulated glucose uptake was greater in soleus muscles of MλKO mice than WT controls. Thus, loss of PKC-λ/ζ activity increases contraction-stimulated muscle glucose uptake. These data clearly demonstrate that PKC-λζ activity is not necessary for contraction-stimulated glucose uptake.
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http://dx.doi.org/10.14814/phy2.12565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673624PMC
November 2015

Moderate voluntary exercise attenuates the metabolic syndrome in melanocortin-4 receptor-deficient rats showing central dopaminergic dysregulation.

Mol Metab 2015 Oct 17;4(10):692-705. Epub 2015 Jul 17.

Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA ; Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.

Objective: Melanocortin-4 receptors (MC4Rs) are highly expressed by dopamine-secreting neurons of the mesolimbic tract, but their functional role has not been fully resolved. Voluntary wheel running (VWR) induces adaptations in the mesolimbic dopamine system and has a myriad of long-term beneficial effects on health. In the present experiments we asked whether MC4R function regulates the effects of VWR, and whether VWR ameliorates MC4R-associated symptoms of the metabolic syndrome.

Methods: Electrically evoked dopamine release was measured in slice preparations from sedentary wild-type and MC4R-deficient Mc4r (K314X) (HOM) rats. VWR was assessed in wild-type and HOM rats, and in MC4R-deficient loxTB (Mc4r) mice, wild-type mice body weight-matched to loxTB (Mc4r) mice, and wild-type mice with intracerebroventricular administration of the MC4R antagonist SHU9119. Mesolimbic dopamine system function (gene/protein expression) and metabolic parameters were examined in wheel-running and sedentary wild-type and HOM rats.

Results: Sedentary obese HOM rats had increased electrically evoked dopamine release in several ventral tegmental area (VTA) projection sites compared to wild-type controls. MC4R loss-of-function decreased VWR, and this was partially independent of body weight. HOM wheel-runners had attenuated markers of intracellular D1-type dopamine receptor signaling despite increased dopamine flux in the VTA. VWR increased and decreased ΔFosB levels in the nucleus accumbens (NAc) of wild-type and HOM runners, respectively. VWR improved metabolic parameters in wild-type wheel-runners. Finally, moderate voluntary exercise corrected many aspects of the metabolic syndrome in HOM runners.

Conclusions: Central dopamine dysregulation during VWR reinforces the link between MC4R function and molecular and behavioral responding to rewards. The data also suggest that exercise can be a successful lifestyle intervention in MC4R-haploinsufficient individuals despite reduced positive reinforcement during exercise training.
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http://dx.doi.org/10.1016/j.molmet.2015.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588435PMC
October 2015

Exercise and Regulation of Carbohydrate Metabolism.

Prog Mol Biol Transl Sci 2015 20;135:17-37. Epub 2015 Aug 20.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA; Department of Medicine, Brigham, and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Carbohydrates are the preferred substrate for contracting skeletal muscles during high-intensity exercise and are also readily utilized during moderate intensity exercise. This use of carbohydrates during physical activity likely played an important role during the survival of early Homo sapiens, and genes and traits regulating physical activity, carbohydrate metabolism, and energy storage have undoubtedly been selected throughout evolution. In contrast to the life of early H. sapiens, modern lifestyles are predominantly sedentary. As a result, intake of excessive amounts of carbohydrates due to the easy and continuous accessibility to modern high-energy food and drinks has not only become unnecessary but also led to metabolic diseases in the face of physical inactivity. A resulting metabolic disease is type 2 diabetes, a complex endocrine disorder characterized by abnormally high concentrations of circulating glucose. This disease now affects millions of people worldwide. Exercise has beneficial effects to help control impaired glucose homeostasis with metabolic disease, and is a well-established tool to prevent and combat type 2 diabetes. This chapter focuses on the effects of exercise on carbohydrate metabolism in skeletal muscle and systemic glucose homeostasis. We will also focus on the molecular mechanisms that mediate the effects of exercise to increase glucose uptake in skeletal muscle. It is now well established that there are different proximal signaling pathways that mediate the effects of exercise and insulin on glucose uptake, and these distinct mechanisms are consistent with the ability of exercise to increase glucose uptake in the face of insulin resistance in people with type 2 diabetes. Ongoing research in this area is aimed at defining the precise mechanism by which exercise increases glucose uptake and insulin sensitivity and the types of exercise necessary for these important health benefits.
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http://dx.doi.org/10.1016/bs.pmbts.2015.07.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4727532PMC
November 2016

Insulin Detemir Is Transported From Blood to Cerebrospinal Fluid and Has Prolonged Central Anorectic Action Relative to NPH Insulin.

Diabetes 2015 Jul 9;64(7):2457-66. Epub 2015 Feb 9.

Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH

Insulin detemir (DET) reduces glycemia comparably to other long-acting insulin formulations but causes less weight gain. Insulin signaling in the brain is catabolic, reducing food intake. We hypothesized that DET reduces weight gain, relative to other insulins, owing to increased transport into the central nervous system and/or increased catabolic action within the brain. Transport of DET and NPH insulin into the cerebrospinal fluid (CSF) was compared over several hours and after the administration of different doses peripherally in rats. DET and NPH had comparable saturable, receptor-mediated transport into the CSF. CSF insulin remained elevated significantly longer after intraperitoneal DET than after NPH. When administered acutely into the 3rd cerebral ventricle, both DET and NPH insulin reduced food intake and body weight at 24 h, and both food intake and body weight remained lower after DET than after NPH after 48 h. In direct comparison with another long-acting insulin, insulin glargine (GLAR), DET led to more prolonged increases in CSF insulin despite a shorter plasma half-life in both rats and mice. Additionally, peripheral DET administration reduced weight gain and increased CSF insulin compared with saline or GLAR in mice. Overall, these data support the hypothesis that DET has distinct effects on energy balance through enhanced and prolonged centrally mediated reduction of food intake.
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http://dx.doi.org/10.2337/db14-1364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477354PMC
July 2015

MGAT2 deficiency and vertical sleeve gastrectomy have independent metabolic effects in the mouse.

Am J Physiol Endocrinol Metab 2014 Dec 14;307(11):E1065-72. Epub 2014 Oct 14.

Metabolic Diseases Institute, University of Cincinnati, Cincinnati, Ohio;

Vertical sleeve gastrectomy (VSG) is currently one of the most effective treatments for obesity. Despite recent developments, the underlying mechanisms that contribute to the metabolic improvements following bariatric surgery remain unresolved. VSG reduces postprandial intestinal triglyceride (TG) production, but whether the effects of VSG on intestinal metabolism are related to metabolic outcomes has yet to be established. The lipid synthesis enzyme acyl CoA:monoacylglycerol acyltransferase-2 (Mogat2; MGAT2) plays a crucial role in the assimilation of dietary fat in the intestine and in regulation of adiposity stores as well. Given the phenotypic similarities between VSG-operated and MGAT2-deficient animals, we reasoned that this enzyme could also have a key role in mediating the metabolic benefits of VSG. However, VSG reduced body weight and fat mass and improved glucose metabolism similarly in whole body MGAT2-deficient (Mogat2(-/-)) mice and wild-type littermates. Furthermore, along with an increase in energy expenditure, surgically naive Mogat2(-/-) mice had altered macronutrient preference, shifting preference away from fat and toward carbohydrates, and increased locomotor activity. Collectively, these data suggest that the beneficial effects of VSG on body weight and glucose metabolism are independent of MGAT2 activity and rather that they are separate from the effects of MGAT2 deficiency. Because MGAT2 inhibitors are proposed as a pharmacotherapeutic option for obesity, our data suggest that, in addition to increasing energy expenditure, shifting macronutrient preference away from fat could be another important mechanism by which these compounds could contribute to weight loss.
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http://dx.doi.org/10.1152/ajpendo.00376.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254982PMC
December 2014

Effect of guanylate cyclase-C activity on energy and glucose homeostasis.

Diabetes 2014 Nov 4;63(11):3798-804. Epub 2014 Jun 4.

Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH.

Uroguanylin is a gastrointestinal hormone primarily involved in fluid and electrolyte handling. It has recently been reported that prouroguanylin, secreted postprandially, is converted to uroguanylin in the brain and activates the receptor guanylate cyclase-C (GC-C) to reduce food intake and prevent obesity. We tested central nervous system administration of two GC-C agonists and found no significant reduction of food intake. We also carefully phenotyped mice lacking the GC-C receptor and found them to have normal body weight, adiposity, and glucose tolerance. Interestingly, uroguanylin knockout mice had a small but significant increase in body weight and adiposity that was accompanied by glucose intolerance. Our data indicate that the modest effects of uroguanylin on energy and glucose homeostasis are not mediated by central GC-C receptors.
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http://dx.doi.org/10.2337/db14-0160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207398PMC
November 2014

Loss of melanocortin-4 receptor function attenuates HPA responses to psychological stress.

Psychoneuroendocrinology 2014 Apr 22;42:98-105. Epub 2014 Jan 22.

Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA.

The melanocortin 4 receptor (MC4R), well-known for its role in the regulation of energy balance, is widely expressed in stress-regulatory brain regions, including the paraventricular nucleus of the hypothalamus (PVH) and the medial amygdala (MeA). In agreement with this, MC4R has been implicated in hypothalamic-pituitary-adrenocortical axis (HPA) regulation. The present work investigated the role of chronic Mc4r function to modulate basal HPA axis tone and to facilitate acute HPA responses to psychological stress, using a novel rat model with Mc4r loss-of-function. In this study, adult male rats were placed into 3 groups (n=15/group) according to genotype [wild-type (WT); heterozygous mutant (HET); and homozygous mutant (HOM)]. Basal (pre-stress) plasma adrenocorticotropic hormone (ACTH) and corticosterone were measured in the AM and PM, and the HPA axis response to restraint was assessed in the AM. Rats were perfused at 2h after restraint to assess the effect of loss of MC4R on stress-induced c-Fos immunolabeling in stress-regulatory brain regions. We find that basal (non-stress) AM and PM plasma ACTH and corticosterone showed a normal diurnal rhythm that was not altered according to genotype. Consistent with this, adrenal and thymus weights were unaffected by genotype. However, the plasma ACTH and corticosterone responses to restraint were significantly reduced by loss of MC4R function. Likewise, stress-induced c-Fos immunolabeling in both PVH and MeA was significantly reduced by loss of Mc4r function. These results support the hypothesis that endogenous MC4R signaling contributes to the HPA axis response to stress. Because MC4R plays a critical role in the regulation of energy balance, the present work suggests that it may also serve as an important communication link between brain metabolic and stress systems.
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http://dx.doi.org/10.1016/j.psyneuen.2014.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4120841PMC
April 2014

Melanocortin MC(4) receptor-mediated feeding and grooming in rodents.

Eur J Pharmacol 2013 Nov 18;719(1-3):192-201. Epub 2013 Jul 18.

Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.

Decades ago it was recognized that the pharmacological profile of melanocortin ligands that stimulated grooming behavior in rats was strikingly similar to that of Xenopus laevis melanophore pigment dispersion. After cloning of the melanocortin MC1 receptor, expressed in melanocytes, and the melanocortin MC4 receptor, expressed mainly in brain, the pharmacological profiles of these receptors appeared to be very similar and it was demonstrated that these receptors mediate melanocortin-induced pigmentation and grooming respectively. Grooming is a low priority behavior that is concerned with care of body surface. Activation of central melanocortin MC4 receptors is also associated with meal termination, and continued postprandial stimulation of melanocortin MC4 receptors may stimulate natural postprandial grooming behavior as part of the behavioral satiety sequence. Indeed, melanocortins fail to suppress food intake or induce grooming behavior in melanocortin MC4 receptor-deficient rats. This review will focus on how melanocortins affect grooming behavior through the melanocortin MC4 receptor, and how melanocortin MC4 receptors mediate feeding behavior. This review also illustrates how melanocortins were the most likely candidates to mediate grooming and feeding based on the natural behaviors they induced.
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http://dx.doi.org/10.1016/j.ejphar.2013.04.060DOI Listing
November 2013

High-fat diet changes the temporal profile of GLP-1 receptor-mediated hypophagia in rats.

Am J Physiol Regul Integr Comp Physiol 2013 Jul 24;305(1):R68-77. Epub 2013 Apr 24.

Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH 45327, USA.

Overconsumption of a high-fat diet promotes weight gain that can result in obesity and associated comorbidities, including Type 2 diabetes mellitus. Consumption of a high-fat diet also alters gut-brain communication. Glucagon-like peptide 1 (GLP-1) is an important gastrointestinal signal that modulates both short- and long-term energy balance and is integral in maintenance of glucose homeostasis. In the current study, we investigated whether high-fat diets (40% or 81% kcal from fat) modulated the ability of the GLP-1 receptor (GLP-1r) agonists exendin-4 (Ex4) and liraglutide to reduce food intake and body weight. We observed that rats maintained on high-fat diets had a delayed acute anorexic response to peripheral administration of Ex4 or liraglutide compared with low-fat diet-fed rats (17% kcal from fat). However, once suppression of food intake in response to Ex4 or liraglutide started, the effect persisted for a longer time in the high-fat diet-fed rats compared with low-fat diet-fed rats. In contrast, centrally administered Ex4 suppressed food intake similarly between high-fat diet-fed and low-fat diet-fed rats. Chronic consumption of a high-fat diet did not change the pharmacokinetics of Ex4 but increased intestinal Glp1r expression and decreased hindbrain Glp1r expression. Taken together, these findings demonstrate that dietary composition alters the temporal profile of the anorectic response to exogenous GLP-1r agonists.
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http://dx.doi.org/10.1152/ajpregu.00588.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3727026PMC
July 2013

Pmch-deficiency in rats is associated with normal adipocyte differentiation and lower sympathetic adipose drive.

PLoS One 2013 26;8(3):e60214. Epub 2013 Mar 26.

Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands.

The orexigenic neuropeptide melanin-concentrating hormone (MCH), a product of Pmch, is an important mediator of energy homeostasis. Pmch-deficient rodents are lean and smaller, characterized by lower food intake, body-, and fat mass. Pmch is expressed in hypothalamic neurons that ultimately are components in the sympathetic nervous system (SNS) drive to white and interscapular brown adipose tissue (WAT, iBAT, respectively). MCH binds to MCH receptor 1 (MCH1R), which is present on adipocytes. Currently it is unknown if Pmch-ablation changes adipocyte differentiation or sympathetic adipose drive. Using Pmch-deficient and wild-type rats on a standard low-fat diet, we analyzed dorsal subcutaneous and perirenal WAT mass and adipocyte morphology (size and number) throughout development, and indices of sympathetic activation in WAT and iBAT during adulthood. Moreover, using an in vitro approach we investigated the ability of MCH to modulate 3T3-L1 adipocyte differentiation. Pmch-deficiency decreased dorsal subcutaneous and perirenal WAT mass by reducing adipocyte size, but not number. In line with this, in vitro 3T3-L1 adipocyte differentiation was unaffected by MCH. Finally, adult Pmch-deficient rats had lower norepinephrine turnover (an index of sympathetic adipose drive) in WAT and iBAT than wild-type rats. Collectively, our data indicate that MCH/MCH1R-pathway does not modify adipocyte differentiation, whereas Pmch-deficiency in laboratory rats lowers adiposity throughout development and sympathetic adipose drive during adulthood.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060214PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608591PMC
September 2013

Angiotensin-converting enzyme inhibition reduces food intake and weight gain and improves glucose tolerance in melanocortin-4 receptor deficient female rats.

Physiol Behav 2013 Sep 13;121:43-8. Epub 2013 Feb 13.

Metabolic Diseases Institute, University of Cincinnati, USA.

Functional loss of melanocortin-4 receptor (MC4R) activity leads to hyperphagia and an obese, glucose intolerant phenotype. We have previously established that inhibition of angiotensin-converting enzyme (ACE) reduces food intake, body weight and glucose homeostasis in diet-induced obesity. The current study assessed the effect of ACE inhibitor treatment in MC4R-deficient female rats on body weight, adiposity and glucose tolerance. Rats homozygous (HOM) for a loss of function Mc4r mutation had an obese phenotype relative to their wildtype (WT) littermates. Inhibition of ACE for 8weeks produced reductions in body weight gain in both HOM and WT rats; however, food intake was only reduced in HOM rats. Weight loss following ACE inhibitor treatment was specific to fat mass while lean mass was unaffected. HOM rats were severely glucose intolerant and insensitive to exogenous insulin injection, and treatment with an ACE inhibitor improved both glucose tolerance and insulin sensitivity in HOM rats although not fully to that of the level of WT rats. The current study indicates that HOM rats are sensitive to the anorectic effects of ACE inhibition, unlike their WT littermates. This resulted in a more rapid reduction in body weight gain and a more substantial loss of adipose mass in HOM animals, relative to WT animals, treated with an ACE inhibitor. Overall, these data demonstrate that MC4R signaling is not required for weight loss following treatment with an ACE inhibitor.
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http://dx.doi.org/10.1016/j.physbeh.2013.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681872PMC
September 2013

Reversal of diet-induced obesity increases insulin transport into cerebrospinal fluid and restores sensitivity to the anorexic action of central insulin in male rats.

Endocrinology 2013 Mar 21;154(3):1047-54. Epub 2013 Jan 21.

Departments of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH 45237, USA.

Diet-induced obesity (DIO) reduces the ability of centrally administered insulin to reduce feeding behavior and also reduces the transport of insulin from the periphery to the central nervous system (CNS). The current study was designed to determine whether reversal of high-fat DIO restores the anorexic efficacy of central insulin and whether this is accompanied by restoration of the compromised insulin transport. Adult male Long-Evans rats were initially maintained on either a low-fat chow diet (LFD) or a high-fat diet (HFD). After 22 weeks, half of the animals on the HFD were changed to the LFD, whereas the other half continued on the HFD for an additional 8 weeks, such that there were 3 groups: 1) a LFD control group (Con; n = 18), 2) a HFD-fed, DIO group (n = 17), and 3) a HFD to LFD, DIO-reversal group (DIO-rev; n = 18). The DIO reversal resulted in a significant reduction of body weight and epididymal fat weight relative to the DIO group. Acute central insulin administration (8 mU) reduced food intake and caused weight loss in Con and DIO-rev but not DIO rats. Fasting cerebrospinal fluid insulin was higher in DIO than Con animals. However, after a peripheral bolus injection of insulin, cerebrospinal fluid insulin increased in Con and DIO-rev rats but not in the DIO group. These data provide support for previous reports that DIO inhibits both the central effects of insulin and insulin's transport to the CNS. Importantly, DIO-rev restored sensitivity to the effects of central insulin on food intake and insulin transport into the CNS.
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http://dx.doi.org/10.1210/en.2012-1929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578991PMC
March 2013

Cell autonomous lipin 1 function is essential for development and maintenance of white and brown adipose tissue.

Mol Cell Biol 2012 Dec 1;32(23):4794-810. Epub 2012 Oct 1.

Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

Through analysis of mice with spatially and temporally restricted inactivation of Lpin1, we characterized its cell autonomous function in both white (WAT) and brown (BAT) adipocyte development and maintenance. We observed that the lipin 1 inactivation in adipocytes of aP2(Cre/+)/Lp(fEx2)(-)(3/fEx2)(-)(3) mice resulted in lipodystrophy and the presence of adipocytes with multilocular lipid droplets. We further showed that time-specific loss of lipin 1 in mature adipocytes in aP2(Cre-ERT2/+)/Lp(fEx2)(-)(3/fEx2)(-)(3) mice led to their replacement by newly formed Lpin1-positive adipocytes, thus establishing a role for lipin 1 in mature adipocyte maintenance. Importantly, we observed that the presence of newly formed Lpin1-positive adipocytes in aP2(Cre-ERT2/+)/Lp(fEx2)(-)(3/fEx2)(-)(3) mice protected these animals against WAT inflammation and hepatic steatosis induced by a high-fat diet. Loss of lipin 1 also affected BAT development and function, as revealed by histological changes, defects in the expression of peroxisome proliferator-activated receptor alpha (PPARα), PGC-1α, and UCP1, and functionally by altered cold sensitivity. Finally, our data indicate that phosphatidic acid, which accumulates in WAT of animals lacking lipin 1 function, specifically inhibits differentiation of preadipocytes. Together, these observations firmly demonstrate a cell autonomous role of lipin 1 in WAT and BAT biology and indicate its potential as a therapeutical target for the treatment of obesity.
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http://dx.doi.org/10.1128/MCB.00512-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3497595PMC
December 2012

Effect of vertical sleeve gastrectomy in melanocortin receptor 4-deficient rats.

Am J Physiol Endocrinol Metab 2012 Jul 24;303(1):E103-10. Epub 2012 Apr 24.

Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA.

Bariatric surgery is currently the most effective treatment for obesity. Vertical sleeve gastrectomy (VSG), a commonly applied bariatric procedure, involves surgically incising most of the volume of the stomach. In humans, partial loss of melanocortin receptor-4 (MC4R) activity is the most common monogenic correlate of obesity regardless of lifestyle. At present it is unclear whether genetic alteration of MC4R signaling modulates the beneficial effects of VSG. Following VSG, we analyzed body weight, food intake, glucose sensitivity, and macronutrient preference of wild-type and MC4R-deficient (Mc4r(+/-) and Mc4r(-/-)) rats compared with sham-operated controls. VSG reduced body weight and fat mass and improved glucose metabolism and also shifted preference toward carbohydrates and away from fat. All of this occurred independently of MC4R activity. In addition, MC4R was resequenced in 46 human subjects who underwent VSG. We observed common genetic variations in the coding sequence of MC4R in five subjects. However, none of those variations appeared to affect the outcome of VSG. Taken together, these data suggest that the beneficial effect of VSG on body weight and glucose metabolism is not mediated by alterations in MC4R activity.
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http://dx.doi.org/10.1152/ajpendo.00159.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404562PMC
July 2012

Gastric bypass surgery attenuates ethanol consumption in ethanol-preferring rats.

Biol Psychiatry 2012 Sep 22;72(5):354-60. Epub 2012 Mar 22.

Department of Psychiatry, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, Ohio 45237, USA.

Background: Roux-en-Y gastric bypass (RYGB) surgery is an effective weight loss strategy employed to treat obesity and associated complications. Importantly, the RYGB procedure has been reported to attenuate reward-related consummatory behaviors. The present work examined the hypothesis that RYGB surgery attenuates ethanol intake and reward in the context of frequent ethanol consumption.

Methods: To do this, self-report of ethanol intake was examined in human bariatric patients (n = 6165) before and following the RYGB procedure. In addition, we utilized a rodent model of RYGB and examined ethanol consumption and ethanol reward in male ethanol-preferring (P) rats, which are selectively bred to consume large volumes of ethanol.

Results: Patients that reported frequent consumption of ethanol before RYGB reported decreased consumption following RYGB surgery. Moreover, the RYGB procedure decreased ethanol intake and the reinforcing properties of ethanol in P rats. Notably, the attenuating effect of RYGB surgery on ethanol consumption was associated with ethanol-induced increases in the gut hormone glucagon-like peptide-1 (GLP-1). Pharmacologic administration of GLP-1 agonists attenuated ethanol consumption in sham P rats. In addition, pharmacologic replacement of the gut hormone ghrelin restored drinking behavior in P rats following RYGB.

Conclusions: Collectively, these findings unveil the potential of RYGB surgery to attenuate ethanol consumption in some humans and rats. Furthermore, our data indicate that this regulation is achieved, in part, through reduction of reward and is modified by the gut hormones GLP-1 and ghrelin.
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http://dx.doi.org/10.1016/j.biopsych.2012.01.035DOI Listing
September 2012

A hypomorphic mutation in Lpin1 induces progressively improving neuropathy and lipodystrophy in the rat.

J Biol Chem 2011 Jul 1;286(30):26781-93. Epub 2011 Jun 1.

Hubrecht Institute-KNAW and University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands.

The Lpin1 gene encodes the phosphatidate phosphatase (PAP1) enzyme Lipin 1, which plays a critical role in lipid metabolism. In this study we describe the identification and characterization of a rat model with a mutated Lpin1 gene (Lpin1(1Hubr)), generated by N-ethyl-N-nitrosourea mutagenesis. Lpin1(1Hubr) rats are characterized by hindlimb paralysis and mild lipodystrophy that are detectable from the second postnatal week. Sequencing of Lpin1 identified a point mutation in the 5'-end splice site of intron 18 resulting in mis-splicing, a reading frameshift, and a premature stop codon. As this mutation does not induce nonsense-mediated decay, it allows the production of a truncated Lipin 1 protein lacking PAP1 activity. Lpin1(1Hubr) rats developed hypomyelination and mild lipodystrophy rather than the pronounced demyelination and adipocyte defects characteristic of Lpin1(fld/fld) mice, which carry a null allele for Lpin1. Furthermore, biochemical, histological, and molecular analyses revealed that these lesions improve in older Lpin1(1Hubr) rats as compared with young Lpin1(1Hubr) rats and Lpin1(fld/fld) mice. We observed activation of compensatory biochemical pathways substituting for missing PAP1 activity that, in combination with a possible non-enzymatic Lipin 1 function residing outside of its PAP1 domain, may contribute to the less severe phenotypes observed in Lpin1(1Hubr) rats as compared with Lpin1(fld/fld) mice. Although we are cautious in making a direct parallel between the presented rodent model and human disease, our data may provide new insight into the pathogenicity of recently identified human LPIN1 mutations.
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http://dx.doi.org/10.1074/jbc.M110.197947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143639PMC
July 2011