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The glucagon-like peptide-1 receptor in the ventromedial hypothalamus reduces short-term food intake in male mice by regulating nutrient sensor activity.

ABSTRACT: Pharmacological activation of the glucagon-like peptide-1 receptor (GLP-1R) in the ventromedial hypothalamus (VMH) reduces food intake. Here, we assessed whether suppression of food intake by GLP-1R agonists (GLP-1RA) in this region is dependent on AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR). We found that pharmacological inhibition of glycolysis, and thus activation of AMPK, in the VMH attenuates the anorectic effect of the GLP-1R agonist exendin-4 (Ex4), indicating that glucose metabolism and inhibition of AMPK are both required for this effect. Furthermore, we found that Ex4-mediated anorexia in the VMH involved mTOR but not acetyl-CoA carboxylase, two downstream targets of AMPK. We support this by showing that Ex4 activates mTOR signaling in the VMH and Chinese hamster ovary (CHO)-K1 cells. In contrast to the clear acute pharmacological impact of the these receptors on food intake, knockdown of the VMH Glp1r conferred no changes in energy balance in either chow- or high-fat-diet-fed mice, and the acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA were preserved. These results show that the VMH GLP-1R regulates food intake by engaging key nutrient sensors but is dispensable for the effects of GLP-1RA on nutrient homeostasis.

SUBMITTER: Burmeister MA

PROVIDER: S-EPMC6109646 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other

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The glucagon-like peptide-1 receptor in the ventromedial hypothalamus reduces short-term food intake in male mice by regulating nutrient sensor activity.

Burmeister Melissa A MA Brown Jacob D JD Ayala Jennifer E JE Stoffers Doris A DA Sandoval Darleen A DA Seeley Randy J RJ Ayala Julio E JE

American journal of physiology. Endocrinology and metabolism 20170815 6

Pharmacological activation of the glucagon-like peptide-1 receptor (GLP-1R) in the ventromedial hypothalamus (VMH) reduces food intake. Here, we assessed whether suppression of food intake by GLP-1R agonists (GLP-1RA) in this region is dependent on AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR). We found that pharmacological inhibition of glycolysis, and thus activation of AMPK, in the VMH attenuates the anorectic effect of the GLP-1R agonist exendin-4 (Ex4), indica ...[more]

PMID: 28811293

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Project description:BackgroundWhile necessary for studying dietary decision-making or public health, estimates of nutrient supply based on self-reported food intake are barely accessible or fully lacking and remain a challenge in human research. In particular, detailed information on dietary fiber is limited. In this study we introduce an automated openly available approach to assess self-reported nutrient intake for research purposes for a popular, validated German food frequency questionnaire (FFQ).MethodsTo this end, we i) developed and shared a code for assessing nutrients (carbohydrates, fat, protein, sugar, fiber, etc.) for 53 items of the quantitative, validated German DEGS1-FFQ questionnaire implementing expert-guided nutritional values of diverse sources with several raters. In a sample of individuals (nGUT-BRAIN = 61 (21 female) overweight, omnivorous), we ii) cross-validated nutrient intake of the last 7 days and the last 24 h and iii) computed test-retest reliability across two timepoints. Further, iv) we reported newly computed nutrient intake for two independent cross-sectional cohorts with continuous weight status and different dietary habits (nMensa = 134 (79 female, 1 diverse), nGREADT = 76 male). Exploratively, we v) correlated computed, energy-adjusted nutrient intake with anthropometric markers and HbA1c and vi) used linear mixed models to analyse the predictability of BMI and WHR by nutrient intake.ResultsIn overweight adults (n = 61 (21 female), mean age 28.2 ± 6.5 years, BMI 27.4 ± 1.6 kg/m2) nutrient intakes were mostly within recommended reference nutrient ranges for both last 7 days and last 24 h. Recommended fiber intake was not reached and sugar intake was surpassed. Calculated energy intake was significantly higher from last 24 h than from last 7 days but energy-adjusted nutrient intakes did not differ between those timeframes. Reliability of nutrient values between last 7 days and 24 h per visit was moderate (Pearson's rhoall ≥ 0.33, rhomax = 0.62) and absolute agreement across two timepoints was low to high for 7 days (Pearson's rhomin = 0.12, rhomax = 0.64,) and low to moderate for 24 h (Pearson's rhomin = 0.11, rhomax = 0.45). Associations of dietary components to anthropometric markers showed distinct sex differences, with overall higher intake by males compared to females and only females presenting a negative association of BMI with fiber intake. Lastly, in the overweight sample (but not when extending the analysis to a wider BMI range of 18.6-36.4 kg/m2), we could confirm that higher BMI was predicted by lower energy-adjusted fiber intake and higher energy-adjusted fat intake (when adjusting for age, sex and physical activity) while higher WHR was predicted by higher energy intake.ConclusionWe provide an openly available tool to systematically assess nutrient intake, including fiber, based on self-report by a common German FFQ. The computed nutrient scores resembled overall plausible and reliable measures of nutrient intake given the known limitations of FFQs regarding over- or underreporting and suggest valid comparability when adjusting for energy intake. Our open code nutrient scoring can help to examine dietary intake in experimental studies, including dietary fiber, and can be readily adapted to other FFQs. Further validation of computed nutrients with biomarkers and nutrient-specific metabolites in serum, urine or feces will help to interpret self-reported dietary intake.

Project description:ObjectiveCentral cholinergic neural circuits play a role in the regulation of feeding behavior. The dorsomedial hypothalamus (DMH) is considered the appetite-stimulating center and contains cholinergic neurons. Here, we study the role of DMH cholinergic neurons in the control of food intake.MethodsTo selectively stimulate DMH cholinergic neurons, we expressed stimulatory designer receptors exclusively activated by designer drugs (DREADDs) and channelrhodopsins in DMH cholinergic neurons by injection of adeno-associated virus (AAV) vectors into the DMH of choline acetyltransferase (ChAT)-IRES-Cre mice. We also generated transgenic mice expressing channelrhodopsins in cholinergic neurons with the Cre-LoxP technique. To delete the Chat gene exclusively in the DMH, we injected an AAV carrying a Cre recombinase transgene into the DMH of floxed ChAT mice. Food intake was measured with and without selective stimulation of DMH cholinergic neurons.ResultsMice lacking the Chat gene in the DMH show reduced body weight as compared to control. Chemogenetic activation of DMH cholinergic neurons promotes food intake. This orexigenic effect is further supported by experiments of optogenetic stimulation of DMH cholinergic neurons. DMH cholinergic neurons innervate pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus (ARC). Treatment with acetylcholine (ACh) enhances GABAergic inhibitory transmission to ARC POMC neurons that is blocked by the muscarinic receptor antagonist. Direct activation of cholinergic fibers in the ARC readily stimulates food intake that is also abolished by the muscarinic receptor antagonist.ConclusionACh released from DMH cholinergic neurons regulates food intake and body weight. This effect is mediated in part through regulation of ARC POMC neurons. Activation of muscarinic receptors on GABAergic axon terminals enhances inhibitory tone to ARC POMC neurons. Hence, this novel DMHACh → ARCPOMC pathway plays an important role in the control of food intake and body weight.

Dataset Information

The glucagon-like peptide-1 receptor in the ventromedial hypothalamus reduces short-term food intake in male mice by regulating nutrient sensor activity.

Publications

The glucagon-like peptide-1 receptor in the ventromedial hypothalamus reduces short-term food intake in male mice by regulating nutrient sensor activity.

Similar Datasets

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