Publications by authors named "Thomas A Lutz"

144 Publications

Effect of high altitude on human postprandial C-octanoate metabolism, intermediary metabolites, gastrointestinal peptides, and visceral perception.

Neurogastroenterol Motil 2021 Aug 2:e14225. Epub 2021 Aug 2.

Division of Hepatology, Department of Medicine II, University Hospital Wurzburg, Germany.

Objective: At high altitude (HA), acute mountain sickness (AMS) is accompanied by neurologic and upper gastrointestinal symptoms (UGS). The primary aim of this study was to test the hypothesis that delayed gastric emptying (GE), assessed by C-octanoate breath testing (OBT), causes UGS in AMS. The secondary aim was to assess post-gastric mechanisms of OBT, which could confound results under these conditions, by determination of intermediary metabolites, gastrointestinal peptides, and basal metabolic rate.

Methods: A prospective trial was performed in 25 healthy participants (15 male) at 4559 m (HA) and at 490 m (Zurich). GE was assessed by OBT (428 kcal solid meal) and UGS by visual analogue scales (VAS). Blood sampling of metabolites (glucose, free fatty acids (FFA), triglycerides (TG), beta-hydroxyl butyrate (BHB), L-lactate) and gastrointestinal peptides (insulin, amylin, PYY, etc.) was performed as well as blood gas analysis and spirometry.

Statistical Analysis: variance analyses, bivariate correlation, and multilinear regression analysis.

Results: After 24 h under hypoxic conditions at HA, participants developed AMS (p < 0.001). CO exhalation kinetics increased (p < 0.05) resulting in reduced estimates of gastric half-emptying times (p < 0.01). However, median resting respiratory quotients and plasma profiles of TG indicated that augmented beta-oxidation was the main predictor of accelerated CO -generation under these conditions.

Conclusion: Quantification of C-octanoate oxidation by a breath test is sensitive to variation in metabolic (liver) function under hypoxic conditions. C-breath testing using short-chain fatty acids is not reliable for measurement of gastric function at HA and should be considered critically in other severe hypoxic conditions, like sepsis or chronic lung disease.
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http://dx.doi.org/10.1111/nmo.14225DOI Listing
August 2021

The calcitonin receptor is the main mediator of LAAMA's body weight lowering effects in male mice.

Eur J Pharmacol 2021 Oct 15;908:174352. Epub 2021 Jul 15.

Institute of Veterinary Physiology, University of Zurich, CH-8057, Zurich, Switzerland.

The anorectic action of the pancreatic hormone amylin is mainly mediated through the area postrema (AP). Amylin activates AP neurons using a heterodimeric receptor (AMY) composed of the calcitonin receptor (CTR) and the receptor activity modifying protein (RAMP 1, 2 or 3). The aim of the following experiments is to test the effects of the long acting amylin analogue (LAAMA) in RAMP1/3 knock-out (KO) male mice and in neuronal CTR KO Nestin-Cre male mice. In vitro, LAAMA exerted an equipotent effect on CTR and AMYs that was maintained across species. Following one week of 45% high fat diet, WT, RAMP1/3 KO and Nestin-Cre mice were injected daily for one week with vehicle or LAAMA. LAAMA decreased body weight gain in WT and in RAMP1/3 KO mice suggesting that RAMP1/3 are not necessary for LAAMA-induced effects. However, LAAMA was not able to produce any body lowering and anorectic effects in Nestin-Cre mice. This was accompanied by the absence of any c-Fos signal in the AP opposite to WT control mice. Together, these results suggest that LAAMA's effects are mainly mediated through CTR rather than specific AMY. The study of LAAMA or any amylin receptor agonist in different receptor KO mouse models helps disentangle the underlying mechanisms used by these molecules.
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http://dx.doi.org/10.1016/j.ejphar.2021.174352DOI Listing
October 2021

A selective role for receptor activity-modifying proteins in subchronic action of the amylin selective receptor agonist NN1213 compared with salmon calcitonin on body weight and food intake in male mice.

Eur J Neurosci 2021 08 9;54(3):4863-4876. Epub 2021 Jul 9.

Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland.

The role of receptor activity-modifying proteins (RAMPs) in modulating the pharmacological effects of an amylin receptor selective agonist (NN1213) or the dual amylin-calcitonin receptor agonist (DACRA), salmon calcitonin (sCT), was tested in three RAMP KO mouse models, RAMP1, RAMP3 and RAMP1/3 KO. Male wild-type (WT) and knockout (KO) littermate mice were fed a 45% high-fat diet for 20 weeks prior to the 3-week treatment period. A decrease in body weight after NN1213 was observed in all WT mice, whereas sCT had no effect. The absence of RAMP1 had no significant effect on NN1213 efficacy, and sCT was still inactive. However, the absence of RAMP3 impeded NN1213 efficacy but improved sCT efficacy. Similar results were observed in RAMP1/3 KO suggesting that the amylin receptor 3 (AMY3 = CTR + RAMP3) is necessary for NN1213's maximal action on body weight and food intake and that the lack of AMY3 allowed sCT to be active. These results suggest that the chronic use of DACRA such as sCT can have unfavourable effect on body weight loss in mice (which differs from the situation in rats), whereas the use of the amylin receptor selective agonist does not. AMY3 seems to play a crucial role in modulating the action of these two compounds, but in opposite directions. The assessment of a long-term effect of amylin and DACRA in different rodent models is necessary to understand potential physiological beneficial and unfavourable effects on weight loss before its transition to clinical trials.
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http://dx.doi.org/10.1111/ejn.15376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457108PMC
August 2021

Hypoglycemia attenuates acute amylin-induced reduction of food intake in male rats.

Physiol Behav 2021 08 29;237:113435. Epub 2021 Apr 29.

Institute of Veterinary Physiology, Vetsuisse Faculty University of Zurich (UZH), 8057 Zurich, Switzerland. Electronic address:

The ability of amylin to inhibit gastric emptying and glucagon secretion in rats is reduced under hypoglycemic conditions. These effects are considered part of a fail-safe mechanism that prevents amylin from further decreasing nutrient supply when blood glucose levels are low. Because these actions and amylin-induced satiation are mediated by the area postrema (AP), it is plausible that these phenomena are based on the co-sensitivity of AP neurons to amylin and glucose. Using hyperinsulinemic glucose clamps in unrestrained and freely-feeding rats, we investigated whether amylin's ability to inhibit food intake is also reduced by hypoglycemia (HYPO). Following an 18 h fast, rats were infused with insulin and glucose for 45 min to clamp blood glucose at baseline levels (between 90 and 100 mg/dL). HYPO (approximately 55 mg/dL) was induced between 45 and 60 min and then maintained for the remainder of the clamp. Rats were injected with amylin (20 µg/kg) or saline and offered normal chow at 85 min. Food intake was measured at 30 and 60 min after amylin. Control hyperinsulinemic/euglycemic (EU) rats were maintained at approximately 150 mg/dL (which is a physiological periprandial glucose level) before and after amylin injection. Terminal experiments tested the effect of amylin to induce the phosphorylation of ERK, a marker of amylin action in the AP, in EU and HYPO conditions. Amylin significantly reduced 30- and 60-min food intake in EU rats, but the effect at 60-min was attenuated in HYPO rats. Interestingly, glucose infusion rate had to be dramatically reduced at meal onset in saline-treated, but not in amylin-treated, EU or HYPO rats; this suggests that meal-related glucose appearance in the blood was inhibited by amylin under both EU and HYPO. Finally, amylin induced a similar pERK response in the AP in EU and HYPO rats. We conclude that amylin's action to decrease eating is blunted in hypoglycemia, and this effect seems to be downstream from amylin-induced pERK in AP neurons. These data allow us to extend the idea of a hypoglycemic brake on amylin's actions to its food intake-reducing effect, but also demonstrate that amylin can buffer meal-induced glucose appearance at EU and HYPO levels.
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http://dx.doi.org/10.1016/j.physbeh.2021.113435DOI Listing
August 2021

Whole-brain mapping of amylin-induced neuronal activity in receptor activity-modifying protein 1/3 knockout mice.

Eur J Neurosci 2021 Apr 27. Epub 2021 Apr 27.

Gubra ApS, Hørsholm, Denmark.

The pancreatic hormone amylin plays a central role in regulating energy homeostasis and glycaemic control by stimulating satiation and reducing food reward, making amylin receptor agonists attractive for the treatment of metabolic diseases. Amylin receptors consist of heterodimerized complexes of the calcitonin receptor and receptor-activity modifying proteins subtype 1-3 (RAMP1-3). Neuronal activation in response to amylin dosing has been well characterized, but only in selected regions expressing high levels of RAMPs. The current study identifies global brain-wide changes in response to amylin and by comparing wild type and RAMP1/3 knockout mice reveals the importance of RAMP1/3 in mediating this response. Amylin dosing resulted in neuronal activation as measured by an increase in c-Fos labelled cells in 20 brain regions, altogether making up the circuitry of neuronal appetite regulation (e.g., area postrema (AP), nucleus of the solitary tract (NTS), parabrachial nucleus (PB), and central amygdala (CEA)). c-Fos response was also detected in distinct nuclei across the brain that typically have not been linked with amylin signalling. In RAMP1/3 knockout amylin induced low-level neuronal activation in seven regions, including the AP, NTS and PB, indicating the existence of RAMP1/3-independent mechanisms of amylin response. Under basal conditions RAMP1/3 knockout mice show reduced neuronal activity in the hippocampal formation as well as reduced hippocampal volume, suggesting a role for RAMP1/3 in hippocampal physiology and maintenance. Altogether these data provide a global map of amylin response in the mouse brain and establishes the significance of RAMP1/3 receptors in relaying this response.
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http://dx.doi.org/10.1111/ejn.15254DOI Listing
April 2021

Serum insulin-like growth factor-1 concentrations in healthy cats before and after weight gain and weight loss.

J Vet Intern Med 2021 May 8;35(3):1274-1278. Epub 2021 Apr 8.

Clinic for Small Animal Internal Medicine, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.

Background: Measurement of serum concentrations of insulin-like growth factor (IGF)-1 is used to diagnose acromegaly in cats.

Hypothesis: Changes of body weight do not affect serum concentrations of IGF-1 in cats.

Animals: Ten healthy purpose-bred cats.

Methods: Prospective study. In lean cats, food availability was stepwise increased during the first week and given ad libitum for a total of 40 weeks to increase their body weight. From week 41 to week 60, food access was limited to reach a weight loss of 1% to 2% each week. Measurement of IGF-1 was performed at week 0, 16, 40, and 60. Insulin-like growth factor-1 was measured by radioimmunoassay. Body weight and IGF-1 were compared among the 4 time points.

Results: Body weight increased by 44% from week 0 (4.5 ± 0.4 kg) to week 40 (6.5 ± 1.2 kg) (P < .001) and decreased by 25% from week 40 to week 60 (4.9 ± 0.7 kg) (P < .001). Serum IGF-1 concentrations did not differ during the study period (week 0, 16, 40, 60: 500 ± 188, 479 ± 247, 470 ± 184, 435 ± 154 ng/mL, respectively; P = .38). Correlations with body weight were not observed.

Conclusions And Clinical Importance: Insulin-like growth factor-1 might not be influenced by changes of body weight in healthy cats, possibly suggesting that the latter is unimportant when interpreting IGF-1 results in this species.
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http://dx.doi.org/10.1111/jvim.16119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163131PMC
May 2021

Hyperleptinemia as a contributing factor for the impairment of glucose intolerance in obesity.

FASEB J 2021 02 23;35(2):e21216. Epub 2020 Nov 23.

Centre for Neuroendocrinology, Department of Physiology, School of Medical Sciences, University of Otago, Dunedin, New Zealand.

Obesity has emerged as a major risk factor for insulin resistance leading to the development of type 2 diabetes (T2D). The condition is characterized by high circulating levels of the adipose-derived hormone leptin and a state of chronic low-grade inflammation. Pro-inflammatory signaling in the hypothalamus is associated with a decrease of central leptin- and insulin action leading to impaired systemic glucose tolerance. Intriguingly, leptin not only regulates body weight and glucose homeostasis but also acts as a pro-inflammatory cytokine. Here we demonstrate that increasing leptin levels (62,5 µg/kg/d, PEGylated leptin) in mice fed a high-fat diet (HFD) exacerbated body weight gain and aggravated hypothalamic micro- as well as astrogliosis. In contrast, administration of a predetermined dose of a long-acting leptin antagonist (100 µg/kg/d, PESLAN) chosen to block excessive leptin signaling during diet-induced obesity (DIO) showed the opposite effect and significantly improved glucose tolerance as well as decreased the total number of microglia and astrocytes in the hypothalamus of mice fed HFD. These results suggest that high levels of leptin, such as in obesity, worsen HFD-induced micro-and astrogliosis, whereas the partial reduction of hyperleptinemia in DIO mice may have beneficial metabolic effects and improves hypothalamic gliosis.
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http://dx.doi.org/10.1096/fj.202001147RDOI Listing
February 2021

Glycemic variability in newly diagnosed diabetic cats treated with the glucagon-like peptide-1 analogue exenatide extended release.

J Vet Intern Med 2020 Nov 1;34(6):2287-2295. Epub 2020 Oct 1.

Clinic for Small Animal Internal Medicine, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.

Background: Glycemic variability (GV) is an indicator of glycemic control and can be evaluated by calculating the SD of blood glucose measurements. In humans with diabetes mellitus (DM), adding a glucagon-like peptide-1 (GLP-1) analogue to conventional therapy reduces GV. In diabetic cats, the influence of GLP-1 analogues on GV is unknown.

Objective: To evaluate GV in diabetic cats receiving the GLP-1 analogue exenatide extended release (EER) and insulin.

Animals: Thirty client-owned cats with newly diagnosed spontaneous DM.

Methods: Retrospective study. Blood glucose curves from a recent prospective placebo-controlled clinical trial generated 1, 3, 6, 10, and 16 weeks after starting therapy were retrospectively evaluated for GV. Cats received either EER (200 μg/kg) or 0.9% saline SC once weekly, insulin glargine and a low-carbohydrate diet. Mean blood glucose concentrations were calculated and GV was assessed by SD. Data were analyzed using nonparametric tests.

Results: In the EER group, GV (mean SD [95% confidence interval]) was lower at weeks 6 (1.69 mmol/L [0.9-2.48]; P = .02), 10 (1.14 mmol/L [0.66-1.62]; P = .002) and 16 (1.66 mmol/L [1.09-2.23]; P = .02) compared to week 1 (4.21 mmol/L [2.48-5.93]) and lower compared to placebo at week 6 (3.29 mmol/L [1.95-4.63]; P = .04) and week 10 (4.34 mmol/L [2.43-6.24]; P < .000). Cats achieving remission (1.21 mmol/L [0.23-2.19]) had lower GV compared to those without remission (2.96 mmol/L [1.97-3.96]; P = .01) at week 6.

Conclusions And Clinical Importance: The combination of EER, insulin, and a low-carbohydrate diet might be advantageous in the treatment of newly diagnosed diabetic cats.
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http://dx.doi.org/10.1111/jvim.15915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694851PMC
November 2020

Noradrenaline signaling in the LPBN mediates amylin's and salmon calcitonin's hypophagic effect in male rats.

FASEB J 2020 11 28;34(11):15448-15461. Epub 2020 Sep 28.

Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland.

The LPBN (lateral parabrachial nucleus) plays an important role in feeding control. CGRP (calcitonin gene-related peptide) LPBN neurons activation mediates the anorectic effects of different gut-derived peptides, including amylin. Amylin and its long acting analog sCT (salmon calcitonin) exert their anorectic actions primarily by directly activating neurons located in the area postrema (AP). A large proportion of projections from the AP and the adjacent nucleus of the solitary tractNTS to the LPBN, are noradrenergic (NA), and amylin-activated NA neurons are critical in mediating amylin's hypophagic effects. Here, we determine the functional role of NA amylin activated neurons to activate CGRP and non-CGRP LPBN neurons. To this end, NA was specifically depleted in the rat LPBN through a stereotaxic microinfusion of 6-OHDA, a neurotoxic agent that destroys NA terminals. While amylin (50 μg/kg) and sCT (5 μg/kg) reduced eating in sham-lesioned rats, no reduction in feeding occurred in NA-depleted animals. Further, the amylin-induced c-Fos response in the LPBN and c-Fos/CGRP colocalization were reduced in NA-depleted animals compared to controls. We conclude that AP → LPBN NA signaling, through the activation of LPBN CGRP neurons, mediates part of amylin's hypophagic effect.
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http://dx.doi.org/10.1096/fj.202001456RRRDOI Listing
November 2020

Systemic and Central Amylin, Amylin Receptor Signaling, and Their Physiological and Pathophysiological Roles in Metabolism.

Compr Physiol 2020 07 8;10(3):811-837. Epub 2020 Jul 8.

Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland.

This article in the Neural and Endocrine Section of Comprehensive Physiology discusses the physiology and pathophysiology of the pancreatic hormone amylin. Shortly after its discovery in 1986, amylin has been shown to reduce food intake as a satiation signal to limit meal size. Amylin also affects food reward, sensitizes the brain to the catabolic actions of leptin, and may also play a prominent role in the development of certain brain areas that are involved in metabolic control. Amylin may act at different sites in the brain in addition to the area postrema (AP) in the caudal hindbrain. In particular, the sensitizing effect of amylin on leptin action may depend on a direct interaction in the hypothalamus. The concept of central pathways mediating amylin action became more complex after the discovery that amylin is also synthesized in certain hypothalamic areas but the interaction between central and peripheral amylin signaling remains currently unexplored. Amylin may also play a dominant pathophysiological role that is associated with the aggregation of monomeric amylin into larger, cytotoxic molecular entities. This aggregation in certain species may contribute to the development of type 2 diabetes mellitus but also cardiovascular disease. Amylin receptor pharmacology is complex because several distinct amylin receptor subtypes have been described, because other neuropeptides [e.g., calcitonin gene-related peptide (CGRP)] can also bind to amylin receptors, and because some components of the functional amylin receptor are also used for other G-protein coupled receptor (GPCR) systems. © 2020 American Physiological Society. Compr Physiol 10:811-837, 2020.
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http://dx.doi.org/10.1002/cphy.c190034DOI Listing
July 2020

Introduction to the special issue "bariatric surgery and appetite".

Appetite 2020 12 1;155:104810. Epub 2020 Aug 1.

Department of Psychiatry, Weill Cornell Medical College, New York, NY, 10025, USA(1). Electronic address:

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http://dx.doi.org/10.1016/j.appet.2020.104810DOI Listing
December 2020

Amylin brain circuitry.

Peptides 2020 10 4;132:170366. Epub 2020 Jul 4.

Institute of Veterinary Physiology, University of Zurich, CH-8057, Zurich, Switzerland. Electronic address:

Amylin is a peptide hormone that is mainly known to be produced by pancreatic β-cells in response to a meal but amylin is also produced by brain cells in discrete brain areas albeit in a lesser amount. Amylin receptor (AMY) is composed of the calcitonin core-receptor (CTR) and one of the 3 receptor activity modifying protein (RAMP), thus forming AMY1-3; RAMP enhances amylin binding properties to the CTR. However, amylin receptor agonist such as salmon calcitonin is able to bind CTR alone. Peripheral amylin's main binding site is located in the area postrema (AP) which then propagate the signal to the nucleus of the solitary tract and lateral parabrachial nucleus (LPBN) and it is then transmitted to the forebrain areas such as central amygdala and bed nucleus of the stria terminalis. Amylin's activation of these different brain areas mediates eating and other metabolic pathways controlling energy expenditure and glucose homeostasis. Peripheral amylin can also bind in the arcuate nucleus of the hypothalamus where it acts independently of the AP to activate POMC and NPY neurons. Amylin activation of NPY neurons has been shown to be transmitted to LPBN neurons to act on eating while amylin POMC signaling affects energy expenditure and locomotor activity. While a large amount of experiments have already been conducted, future studies will have to further investigate how amylin is taken up by forebrain areas and deepen our understanding of amylin action on peripheral metabolism.
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http://dx.doi.org/10.1016/j.peptides.2020.170366DOI Listing
October 2020

Viral depletion of calcitonin receptors in the area postrema: A proof-of-concept study.

Physiol Behav 2020 09 1;223:112992. Epub 2020 Jun 1.

Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich (UZH), 8057 Zurich, Switzerland.

The area postrema (AP), located in the caudal hindbrain, is one of the primary binding sites for the endocrine satiation hormone amylin. Amylin is co-secreted with insulin from pancreatic ß-cells and binds to heterodimeric receptors that consist of a calcitonin core receptor (CTR) paired with receptor-activity modifying protein (RAMP) 1 or 3. In this study, we aim to validate a CTR-floxed (CTR) mouse model for the functional and site-specific depletion of amylin/CTR signaling in the AP and the nucleus tractus solitarius (NTS). CTR mice were injected in the NTS with adeno-associated virus (AAV) containing a green fluorescent protein tag (GFP) and Cre recombinase to create a locally restricted knockout of CTR in the caudal hindbrain. KO mice showed a lack of c-Fos expression, a marker for neuronal activation, in the AP, NTS and LPBN after amylin injection. The effect of amylin and salmon calcitonin (sCT), an amylin receptor agonist, on food intake was blunted in KO mice, confirming a functional reduction of amylin signaling in the hindbrain.
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http://dx.doi.org/10.1016/j.physbeh.2020.112992DOI Listing
September 2020

Oleoylethanolamide decreases frustration stress-induced binge-like eating in female rats: a novel potential treatment for binge eating disorder.

Neuropsychopharmacology 2020 10 30;45(11):1931-1941. Epub 2020 Apr 30.

Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, P.le Aldo Moro 5, 00185, Rome, Italy.

Binge eating disorder (BED) is the most frequent eating disorder, for which current pharmacotherapies show poor response rates and safety concerns, thus highlighting the need for novel treatment options. The lipid-derived messenger oleoylethanolamide (OEA) acts as a satiety signal inhibiting food intake through the involvement of central noradrenergic and oxytocinergic neurons. We investigated the anti-binge effects of OEA in a rat model of binge-like eating, in which, after cycles of intermittent food restrictions/refeeding and palatable food consumptions, female rats show a binge-like intake of palatable food, following a 15-min exposure to their sight and smell ("frustration stress"). Systemically administered OEA dose-dependently (2.5, 5, and 10 mg kg) prevented binge-like eating. This behavioral effect was associated with a decreased activation (measured by mapping the expression of c-fos, an early gene widely used as a marker of cellular activation) of brain areas responding to stress (such as the nucleus accumbens and amygdala) and to a stimulation of areas involved in the control of food intake, such as the VTA and the PVN. These effects were paralleled, also, to the modulation of monoamine transmission in key brain areas involved in both homeostatic and hedonic control of eating. In particular, a decreased dopaminergic response to stress was observed by measuring dopamine extracellular concentrations in microdialysates from the nucleus accumbens shell, whereas an increased serotonergic and noradrenergic tone was detected in tissue homogenates of selected brain areas. Finally, a decrease in corticotropin-releasing factor (CRF) mRNA levels was induced by OEA in the central amygdala, while an increase in oxytocin mRNA levels was induced in the PVN. The restoration of a normal oxytocin receptor density in the striatum paralleled the oxytocinergic stimulation produced by OEA. In conclusion, we provide evidence suggesting that OEA might represent a novel potential pharmacological target for the treatment of binge-like eating behavior.
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http://dx.doi.org/10.1038/s41386-020-0686-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609309PMC
October 2020

An Overview of Rodent Models of Obesity and Type 2 Diabetes.

Authors:
Thomas A Lutz

Methods Mol Biol 2020 ;2128:11-24

Institute of Veterinary Physiology, Vetsuisse Faculty University of Zurich, Zurich, Switzerland.

Many animal models that are currently used in appetite and obesity research share at least some main features of human obesity and its comorbidities. Hence, even though no animal model replicates all aspects of "common" human obesity, animal models are imperative in studying the control of energy balance and reasons for its imbalance that may eventually lead to overt obesity. The most frequently used animal models are small rodents that may be based on mutations or manipulations of individual or several genes and on the exposure to obesogenic diets or other manipulations that predispose the animals to gaining or maintaining excessive weight. Characteristics include hyperphagia or changes in energy metabolism and at least in some models the frequent comorbidities of obesity, like hyperglycemia, insulin resistance, or diabetes-like syndromes. Some of the most frequently used animal models of obesity research involve animals with monogenic mutations of the leptin pathway which in fact are useful to study specific mechanistic aspects of eating controls, but typically do not recapitulate "common" obesity in the human population. Hence, this review will mention advantages and disadvantages of respective animal models in order to build a basis for the most appropriate use in biomedical research.
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http://dx.doi.org/10.1007/978-1-0716-0385-7_2DOI Listing
March 2021

Amylin/Calcitonin Receptor-Mediated Signaling in POMC Neurons Influences Energy Balance and Locomotor Activity in Chow-Fed Male Mice.

Diabetes 2020 06 9;69(6):1110-1125. Epub 2020 Mar 9.

Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland

Amylin, a pancreatic hormone and neuropeptide, acts principally in the hindbrain to decrease food intake and has recently been shown to act as a neurotrophic factor to control the development of area postrema → nucleus of the solitary tract and arcuate hypothalamic nucleus → paraventricular nucleus axonal fiber outgrowth. Amylin is also able to activate ERK signaling specifically in POMC neurons independently of leptin. For investigation of the physiological role of amylin signaling in POMC neurons, the core component of the amylin receptor, calcitonin receptor (CTR), was depleted from POMC neurons using an inducible mouse model. The loss of CTR in POMC neurons leads to increased body weight gain, increased adiposity, and glucose intolerance in male knockout mice, characterized by decreased energy expenditure (EE) and decreased expression of uncoupling protein 1 (UCP1) in brown adipose tissue. Furthermore, a decreased spontaneous locomotor activity and absent thermogenic reaction to the application of the amylin receptor agonist were observed in male and female mice. Together, these results show a significant physiological impact of amylin/calcitonin signaling in CTR-POMC neurons on energy metabolism and demonstrate the need for sex-specific approaches in obesity research and potentially treatment.
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http://dx.doi.org/10.2337/db19-0849DOI Listing
June 2020

Vaccination Against Amyloidogenic Aggregates in Pancreatic Islets Prevents Development of Type 2 Diabetes Mellitus.

Vaccines (Basel) 2020 Mar 2;8(1). Epub 2020 Mar 2.

Department of Rheumatology, Immunology and Allergology (RIA), University Hospital, University of Bern, 3010 Bern, Switzerland.

Type 2 diabetes mellitus (T2DM) is a chronic progressive disease characterized by insulin resistance and insufficient insulin secretion to maintain normoglycemia. The majority of T2DM patients bear amyloid deposits mainly composed of islet amyloid polypeptide (IAPP) in their pancreatic islets. These-originally β-cell secretory products-extracellular aggregates are cytotoxic for insulin-producing β-cells and are associated with β-cell loss and inflammation in T2DM advanced stages. Due to the absence of T2DM preventive medicaments and the presence of only symptomatic drugs acting towards increasing hormone secretion and action, we aimed at establishing a novel disease-modifying therapy targeting the cytotoxic IAPP deposits in order to prevent the development of T2DM. We generated a vaccine based on virus-like particles (VLPs), devoid of genomic material, coupled to IAPP peptides inducing specific antibodies against aggregated, but not monomeric IAPP. Using a mouse model of islet amyloidosis, we demonstrate in vivo that our vaccine induced a potent antibody response against aggregated, but not soluble IAPP, strikingly preventing IAPP depositions, delaying onset of hyperglycemia and the induction of the associated pro-inflammatory cytokine Interleukin 1β (IL-1β). We offer the first cost-effective and safe disease-modifying approach targeting islet dysfunction in T2DM, preventing pathogenic aggregates without disturbing physiological IAPP function.
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http://dx.doi.org/10.3390/vaccines8010116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157615PMC
March 2020

Oxidative status of erythrocytes, hyperglycemia, and hyperlipidemia in diabetic cats.

J Vet Intern Med 2020 Mar 16;34(2):616-625. Epub 2020 Feb 16.

Clinic for Small Animal Internal Medicine, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.

Background: Erythrocytes of diabetic cats have decreased superoxide dismutase activity, possibly indicative of oxidative stress.

Hypothesis: Erythrocytes of diabetic cats undergo oxidative stress, which is caused by hyperglycemia and hyperlipidemia, and improves with treatment.

Animals: Twenty-seven client-owned cats with diabetes mellitus, 11 matched healthy cats, and 21 purpose-bred healthy cats.

Methods: Prospective study. Advanced oxidized protein products, carbonyls (protein oxidation by-products), and thiols (antioxidants) were quantified in erythrocyte membrane, thiobarbituric acid reactive substances (TBAR, lipid peroxidation by-products), and thiols in erythrocyte cytoplasm of all cats. Comparison were performed between diabetic and matched healthy cats, between diabetic cats achieving remission or not, and among purpose-bred cats after 10 days of hyperglycemia (n = 5) or hyperlipidemia (n = 6) versus controls treated with saline (n = 5) or untreated (n = 5).

Results: Compared with controls, erythrocytes of diabetic cats initially had higher median membrane carbonyls (4.6 nmol/mg total protein [range: 0.1-37.7] versus 0.7 [0.1-4.7], P < .001) and lower cytoplasmic TBAR (1.9 nmol/mg [0.5-2.4] versus 2.4 [1.4-3.5] P < .001), and thiols (419 nmol/mg [165-621] versus 633 [353-824], P < 0.001). After 12-16 weeks of treatment in diabetic cats, carbonyls decreased by 13% (P < .001), but remained higher (P < .001) and TBAR and thiols lower (P = .02, P < .001) than those in controls. No differences were observed between diabetic cats achieving remission or not, and among purpose-bred cats.

Conclusions And Clinical Importance: Diabetes mellitus is associated with increased protein oxidation and reduced antioxidant defenses, which persist during treatment and remission, although mild improvement in protein oxidation occurs. Short-term hyperglycemia or hyperlipidemia does not cause oxidative stress. The reason for decreased TBAR remains unknown.
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http://dx.doi.org/10.1111/jvim.15732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096612PMC
March 2020

Diabetic remission in a cat treated with an implantable pump to deliver insulin.

Can Vet J 2020 01;61(1):30-34

Istituto Veterinario di Novara, Strada Provinciale 9, 28060 Granozzo con Monticello (NO), Italy (Crinò, Iavazzo, Ferri, Zini); Department of Animal Medicine, Production and Health, viale dell'Università 16, 35020 Legnaro (PD), University of Padova, Italy (Coppola, Zini); Clinic for Small Animal Internal Medicine (Salesov, Reusch, Zini); and Institute of Veterinary Physiology (Lutz), Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260, 8057 Zurich, Switzerland.

A diabetic cat was referred because of poor metabolic control and difficulties the owner experienced injecting insulin. A pump, telemetrically controlled with a smartphone, was implanted subcutaneously to deliver insulin. Before implantation, the pump reservoir was filled with a rapid-acting human recombinant insulin. The insulin was administered through continuous infusion or periodic boluses over 2 weeks while the cat was hospitalized and over another 2 weeks after discharge from the hospital. Adjustments of insulin dosage were performed based on blood glucose concentrations measured with a continuous blood monitoring system (CGMS). The cat achieved diabetic remission that is still lasting after 1 year. The treatment protocol adopted in this cat contributed to achieving remission. The owner's unwillingness to inject insulin into an uncooperative cat was circumvented with the implantable pump. Key clinical message: The implantable subcutaneous pump, telemetrically controlled by a smartphone, easily allowed the clinician to modify the type of administration and the amount of insulin delivered; the concurrent use of a CGMS allowed detection of sudden changes in blood glucose while limiting stress to the cat.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909408PMC
January 2020

RAMP1 and RAMP3 Differentially Control Amylin's Effects on Food Intake, Glucose and Energy Balance in Male and Female Mice.

Neuroscience 2020 11 24;447:74-93. Epub 2019 Dec 24.

Institute of Veterinary Physiology, University of Zurich, Winterthurerstrasse 260, 8057 Zurich, Switzerland. Electronic address:

Amylin is a pancreatic peptide, which acts as a key controller of food intake and energy balance and predominately binds to three receptors (AMY 1-3). AMY 1-3 are composed of a calcitonin core receptor (CTR) and associated receptor-activity modifying proteins (RAMPs) 1-3. Using RAMP1, RAMP3 and RAMP1/3 global KO mice, this study aimed to determine whether the absence of one or two RAMP subunits affects food intake, glucose homeostasis and metabolism. Of all the RAMP-deficient mice, only high-fat diet fed RAMP1/3 KO mice had increased body weight. Chow-fed RAMP3 KO and high-fat diet fed 1/3 KO male mice were glucose intolerant. Fat depots were increased in RAMP1 KO male mice. No difference in energy expenditure was observed but the respiratory exchange ratio (RER) was elevated in RAMP1/3 KO. RAMP1 and 1/3 KO male mice displayed an increase in intermeal interval (IMI) and meal duration, whereas IMI was decreased in RAMP3 KO male and female mice. WT and RAMP1, RAMP3, and RAMP1/3 KO male and female littermates were then assessed for their food intake response to an acute intraperitoneal injection of amylin or its receptor agonist, salmon calcitonin (sCT). RAMP1/3 KO were insensitive to both, while RAMP3 KO were responsive to sCT only and RAMP1 KO to amylin only. While female mice generally weighed less than male mice, only RAMP1 KO showed a clear sex difference in meal pattern and food intake tests. Lastly, a decrease in CTR fibers did not consistently correlate with a decrease in amylin- induced c-Fos expression in the area postrema (AP). Ultimately, the results from this study provide evidence for a role of RAMP1 in mediation of fat utilization and a role for RAMP3 in glucose homeostasis and amylin's anorectic effect.
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http://dx.doi.org/10.1016/j.neuroscience.2019.11.036DOI Listing
November 2020

Evaluation of Acute Mountain Sickness by Unsedated Transnasal Esophagogastroduodenoscopy at High Altitude.

Clin Gastroenterol Hepatol 2020 09 25;18(10):2218-2225.e2. Epub 2019 Nov 25.

Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland; Department of Medicine, GZO - Zurich Regional Health Center, Wetzikon, Switzerland. Electronic address:

Background & Aims: It is not clear how rapid ascent to a high altitude causes the gastrointestinal symptoms of acute mountain sickness (AMS). We assessed the incidence of endoscopic lesions in the upper gastrointestinal tract in healthy mountaineers after a rapid ascent to high altitude, their association with symptoms, and their pathogenic mechanisms.

Methods: In a prospective study, 25 mountaineers (10 women; mean age, 43.8 ± 9.5 y) underwent unsedated, transnasal esophagogastroduodenoscopy in Zurich (490 m) and then on 2 test days (days 2 and 4) at a high altitude laboratory in the Alps (Capanna Regina Margherita, 4559 m). Symptoms were assessed using validated instruments for AMS (the acute mountain sickness score and the Lake Louise scoring system) and visual analogue scales (scale, 0-100). Levels of messenger RNAs (mRNAs) in duodenal biopsy specimens were measured by quantitative polymerase chain rection.

Results: The follow-up endoscopy at high altitude was performed in 19 of 25 patients on day 2 and in 23 of 25 patients on day 4. The frequency of endoscopic lesions increased from 12% at baseline to 26.3% on day 2 and to 60.9% on day 4 (P < .001). The incidence of ulcer disease increased from 0 at baseline to 10.5% on day 2 and to 21.7% on day 4 (P = .014). Mucosal lesions were associated with lower hunger scores (37.3 vs 67.4 in patients without lesions; P = .012). Subjects with peptic lesions had higher levels of HIF2A mRNA, which encodes a hypoxia-induced transcription factor, and ICAM1 mRNA, which encodes an adhesion molecule, compared with subjects without lesions (fold changes, 1.38 vs 0.63; P = .001; and 1.37 vs 0.66; P = .011, respectively).

Conclusions: In a prospective study of 25 mountaineers, fast ascent to a high altitude resulted in rapid onset of clinically meaningful mucosal lesions and ulcer disease. Duodenal biopsy specimens from these subjects had increased levels of HIF2A mRNA and ICAM1 mRNA, which might contribute to the formation of hypoxia-induced peptic lesions. Further studies are needed of the mechanisms of this process.
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http://dx.doi.org/10.1016/j.cgh.2019.11.036DOI Listing
September 2020

Introduction to the special issue "Bariatric Surgery and Appetite".

Appetite 2020 03 13;146:104515. Epub 2019 Nov 13.

Department of Psychiatry, Weill Cornell Medical College, New York, NY, 10025, USA. Electronic address:

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http://dx.doi.org/10.1016/j.appet.2019.104515DOI Listing
March 2020

Unsilencing of native LepRs in hypothalamic SF1 neurons does not rescue obese phenotype in LepR-deficient mice.

Am J Physiol Regul Integr Comp Physiol 2019 09 17;317(3):R451-R460. Epub 2019 Jul 17.

Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.

Leptin receptor (LepR) signaling in neurons of the ventromedial nucleus of the hypothalamus (VMH), specifically those expressing steroidogenic factor-1 (SF1), have been proposed to play a key role in controlling energy balance. By crossing LepR-silenced (LepR) mice with those expressing SF1-Cre, we unsilenced native LepR specifically in the VMH and tested whether SF1 neurons in the VMH are critical mediators of leptin's effect on energy homeostasis. LepR × SF1-Cre [knockout (KO)/Tg+] mice were metabolically phenotyped and compared with littermate controls that either expressed or were deficient in LepRs. Leptin-induced phosphorylated STAT3 was present in the VMH of KO/Tg+ mice and absent in other hypothalamic nuclei. VMH leptin signaling did not ameliorate obesity resulting from LepR deficiency in chow-fed mice. There was no change in food intake or energy expenditure when comparing complete LepR-null mice with KO/Tg+ mice, nor did KO/Tg+ mice show improved glucose tolerance. The presence of functional LepRs in the VMH mildly enhanced sensitivity to the pancreatic hormone amylin. When maintained on a high-fat diet (HFD), there was no reduction in diet-induced obesity in KO/Tg+ mice, but KO/Tg+ mice had improved glucose tolerance after 7 wk on an HFD compared with LepR-null mice. We conclude that LepR signaling in the VMH alone is not sufficient to correct metabolic dysfunction observed in LepR-null mice.
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http://dx.doi.org/10.1152/ajpregu.00111.2019DOI Listing
September 2019

Body weight-dependent and independent improvement in lipid metabolism after Roux-en-Y gastric bypass in ApoE*3Leiden.CETP mice.

Int J Obes (Lond) 2019 12 3;43(12):2394-2406. Epub 2019 Jul 3.

Institute of Veterinary Physiology, Vetsuisse Faculty University of Zurich, Zurich, Switzerland.

Background/objectives: The incidence of obesity and metabolic syndrome (MetS) has rapidly increased worldwide. Roux-en-Y gastric bypass (RYGB) achieves long-term weight loss and improves MetS-associated comorbidities. Using a mouse model with a humanized lipoprotein metabolism, we elucidated whether improvements in lipid and glucose metabolism after RYGB surgery are body weight loss-dependent or not.

Subjects/methods: Male ApoE*3Leiden.CETP (ApoE3L.CETP) mice fed Western type diet for 6 weeks underwent RYGB or Sham surgery. Sham groups were either fed ad libitum or were body weight-matched (BWm) to the RYGB mice to discriminate surgical effects from body weight loss-associated effects. Before and after surgery, plasma was collected to assess the metabolic profile, and glucose tolerance and insulin sensitivity were tested. Twenty days after surgery, mice were sacrificed, and liver was collected to assess metabolic, histological and global gene expression changes after surgery.

Results: RYGB induced a marked reduction in body weight, which was also achieved by severe food restriction in BWm mice, and total fat mass compared to Sham ad libitum mice (Sham AL). Total cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C) and ceramide were strongly reduced 20 days after surgery in RYGB compared to BWm mice. Glucose tolerance and insulin sensitivity improved 13 days after surgery similarly in RYGB and BWm mice. Liver histology confirmed lipid reduction in RYGB and BWm mice while the transcriptomics data indicated altered genes expression in lipid metabolism.

Conclusions: RYGB surgery improves glucose metabolism and greatly ameliorates lipid metabolism in part in a body weight-dependent manner. Given that ApoE3L.CETP mice were extensively studied to describe the MetS, and given that RYGB improved ceramide after surgery, our data confirmed the usefulness of ApoE3L.CETP mice after RYGB in deciphering the metabolic improvements to treat the MetS.
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http://dx.doi.org/10.1038/s41366-019-0408-yDOI Listing
December 2019

Gastric bypass surgery in lean adolescent mice prevents diet-induced obesity later in life.

Sci Rep 2019 05 27;9(1):7881. Epub 2019 May 27.

Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA.

Gastric bypass surgery is the most effective treatment and is often the only option for subjects with severe obesity. However, investigation of critical molecular mechanisms involved has been hindered by confounding of specific effects of surgery and side effects associated with acute surgical trauma. Here, we dissociate the two components by carrying out surgery in the lean state and testing its effectiveness to prevent diet-induced obesity later in life. Body weight and composition of female mice with RYGB performed at 6 weeks of age were not significantly different from sham-operated and age-matched non-surgical mice at the time of high-fat diet exposure 12 weeks after surgery. These female mice were completely protected from high-fat diet-induced obesity and accompanying metabolic impairments for up to 50 weeks. Similar effects were seen in male mice subjected to RYGB at 5-6 weeks, although growth was slightly inhibited and protection from diet-induced obesity was less complete. The findings confirm that RYGB does not indiscriminately lower body weight but specifically prevents excessive diet-induced obesity and ensuing metabolic impairments. This prevention of obesity model should be crucial for identifying the molecular mechanisms underlying gastric bypass surgery.
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http://dx.doi.org/10.1038/s41598-019-44344-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536499PMC
May 2019

Significant changes in hepatic transcriptome and circulating miRNAs are associated with diet-induced metabolic syndrome in apoE3L.CETP mice.

J Cell Physiol 2019 11 23;234(11):20485-20500. Epub 2019 Apr 23.

Laboratory of Biochemistry, Division of Basic Sciences, University of Crete Medical School, Heraklion, Greece.

Long-term exposure to excess dietary fat leads to obesity and the metabolic syndrome (MetS). The purpose of the present study was to identify global changes in liver gene expression and circulating miRNAs in a humanized mouse model of diet-induced MetS. Male apoE3L.CETP mice received a high-fat diet (HFD) or a low-fat diet (LFD) for different time periods and the progression of MetS pathology was monitored. A separate group of mice was divided into responders (R) or nonresponders (NR) and received HFD for 16 weeks. We found that mice receiving the HFD developed manifestations of MetS and displayed an increasing number of differentially expressed transcripts at 4, 8, and 12 weeks compared with mice receiving the LFD. Significantly changed genes were functionally annotated to metabolic diseases and pathway analysis revealed the downregulation of genes in cholesterol and fatty acid biosynthesis and upregulation of genes related to lipid droplet formation, which was in line with the development of hepatic steatosis. In the serum of the apoE3L.CETP mice we identified three miRNAs that were upregulated specifically in the HFD group. We found that responder mice have a distinct gene signature that differentiates them from nonresponders. Comparison of the two diet intervention studies revealed a limited number of common differentially expressed genes but the expression of these common genes was affected in a similar way in both studies. In conclusion, the characteristic hepatic gene signatures and serum miRNAs identified in the present study provide novel insights to MetS pathology and could be exploited for diagnostic or therapeutic purposes.
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http://dx.doi.org/10.1002/jcp.28649DOI Listing
November 2019

Endogenous amylin contributes to birth of microglial cells in arcuate nucleus of hypothalamus and area postrema during fetal development.

Am J Physiol Regul Integr Comp Physiol 2019 06 3;316(6):R791-R801. Epub 2019 Apr 3.

Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich , Zurich , Switzerland.

Amylin acts in the area postrema (AP) and arcuate nucleus (ARC) to control food intake. Amylin also increases axonal fiber outgrowth from the AP→nucleus tractus solitarius and from ARC→hypothalamic paraventricular nucleus. More recently, exogenous amylin infusion for 4 wk was shown to increase neurogenesis in adult rats in the AP. Furthermore, amylin has been shown to enhance leptin signaling in the ARC and ventromedial nucleus of the hypothalamus (VMN). Thus, we hypothesized that endogenous amylin could be a critical factor in regulating cell birth in the ARC and AP and that amylin could also be involved in the birth of leptin-sensitive neurons. Amylin dams were injected with BrdU at and at ; BrdU+ cells were quantified in wild-type (WT) and amylin knockout (KO) mice. The number of BrdU+HuC/D+ neurons was similar in ARC and AP, but the number of BrdU+Iba1+ microglia was significantly decreased in both nuclei. Five-week-old WT and KO littermates were injected with leptin to test whether amylin is involved in the birth of leptin-sensitive neurons. Although there was no difference in the number of BrdU+c-Fos+ neurons in the ARC and dorsomedial nucleus, an increase in BrdU+c-Fos+ neurons was seen in VMN and lateral hypothalamus (LH) in amylin KO mice. In conclusion, these data suggest that during fetal development, endogenous amylin favors the birth of microglial cells in the ARC and AP and that it decreases the birth of leptin-sensitive neurons in the VMN and LH.
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http://dx.doi.org/10.1152/ajpregu.00004.2019DOI Listing
June 2019

Diabetic cats have decreased gut microbial diversity and a lack of butyrate producing bacteria.

Sci Rep 2019 03 18;9(1):4822. Epub 2019 Mar 18.

University of Copenhagen, Department of Veterinary Clinical Sciences, Dyrlaegevej 16, DK-1870, Frederiksberg C, Denmark.

Obesity and inactivity are major risk factors of feline diabetes mellitus (FDM) and human type II diabetes mellitus (T2DM). In recent years, changes in the gut microbiota have been suggested as a contributing factor to T2DM. Whether the gut microbiota (GM) composition plays a role in FDM remains unknown. The aim of the current study was firstly a cross-sectional comparison of the GM of diabetic cats, to that of lean, and of obese/overweight non-diabetic cats of a similar age. Specifically, fecal samples from 82 privately-owned cats from Denmark and Switzerland were sequenced using 16S rRNA gene amplicon metabarcoding. Secondly dietary intervention data was generated, by obtaining additional samples from a subset of cats after placing them on a high-protein diet for four weeks. The GM diversity of diabetic cats was lower than that of lean cats in the cross-sectional study, and lower compared to lean and to overweight/obese cats after diet intervention. Diabetic cats also exhibited fewer Anaerotruncus, Dialister, and unknown Ruminococcaceae than lean cats. Serum fructosamine levels correlated negatively with Prevotellaceae abundance and positively with Enterobacteriaceae abundance. In summary the intestinal microbiota of diabetic cats was characterized by decreased GM diversity and loss of butyrate producing bacterial genera.
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http://dx.doi.org/10.1038/s41598-019-41195-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423039PMC
March 2019

High-throughput screening for selective appetite modulators: A multibehavioral and translational drug discovery strategy.

Sci Adv 2018 10 31;4(10):eaav1966. Epub 2018 Oct 31.

Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.

How appetite is modulated by physiological, contextual, or pharmacological influence is still unclear. Specifically, the discovery of appetite modulators is compromised by the abundance of side effects that usually limit in vivo drug action. We set out to identify neuroactive drugs that trigger only their intended single behavioral change, which would provide great therapeutic advantages. To identify these ideal bioactive small molecules, we quantified the impact of more than 10,000 compounds on an extended series of different larval zebrafish behaviors using an in vivo imaging strategy. Known appetite-modulating drugs altered feeding and a pleiotropy of behaviors. Using this multibehavioral strategy as an active filter for behavioral side effects, we identified previously unidentified compounds that selectively increased or reduced food intake by more than 50%. The general applicability of this strategy is shown by validation in mice. Mechanistically, most candidate compounds were independent of the main neurotransmitter systems. In addition, we identified compounds with multibehavioral impact, and correlational comparison of these profiles with those of known drugs allowed for the prediction of their mechanism of action. Our results illustrate an unbiased and translational drug discovery strategy for ideal psychoactive compounds and identified selective appetite modulators in two vertebrate species.
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http://dx.doi.org/10.1126/sciadv.aav1966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209392PMC
October 2018

Rodent models of leptin receptor deficiency are less sensitive to amylin.

Am J Physiol Regul Integr Comp Physiol 2018 10 22;315(4):R856-R865. Epub 2018 Aug 22.

Institute of Veterinary Physiology, Vetsuisse Faculty University of Zurich , Zurich , Switzerland.

The pancreatic hormone amylin is released from beta cells following nutrient ingestion and contributes to the control of body weight and glucose homeostasis. Amylin reduces food intake by activating neurons in the area postrema (AP). Amylin was also shown to synergize with the adipokine leptin, with combination therapy producing greater weight loss and food intake reduction than either hormone alone. Although amylin and leptin were initially thought to interact downstream of the AP in the hypothalamus, recent findings show that the two hormones can act on the same AP neurons, suggesting a more direct relationship. The objective of this study was to determine whether amylin action depends on functional leptin signaling. We tested the ability of amylin to induce satiation and to activate its primary target neurons in the AP in two rodent models of LepR deficiency, the db/db mouse and the Zucker diabetic fatty (ZDF) rat. When compared with wild-type (WT) mice, db/db mice exhibited reduced amylin-induced satiation, reduced amylin-induced Fos in the AP, and a lower expression of calcitonin receptor (CTR) protein, the core component of all amylin receptors. ZDF rats also showed no reduction in food intake following amylin treatment; however, unlike the db/db mice, levels of amylin-induced Fos and CTR in the AP were no different than WT rats. Our results suggest that LepR expression is required for the full anorexic effect of amylin; however, the neuronal activation in the AP seems to depend on the type of LepR mutation.
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http://dx.doi.org/10.1152/ajpregu.00179.2018DOI Listing
October 2018
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