Dataset Information

The Hypothalamic Glucagon-Like Peptide 1 Receptor Is Sufficient but Not Necessary for the Regulation of Energy Balance and Glucose Homeostasis in Mice.

ABSTRACT: Pharmacological activation of the hypothalamic glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) promotes weight loss and improves glucose tolerance. This demonstrates that the hypothalamic GLP-1R is sufficient but does not show whether it is necessary for the effects of exogenous GLP-1R agonists (GLP-1RA) or endogenous GLP-1 on these parameters. To address this, we crossed mice harboring floxed Glp1r alleles to mice expressing Nkx2.1-Cre to knock down Glp1r expression throughout the hypothalamus (GLP-1RKD?Nkx2.1cre). We also generated mice lacking Glp1r expression specifically in two GLP-1RA-responsive hypothalamic feeding nuclei/cell types, the paraventricular nucleus (GLP-1RKD?Sim1cre) and proopiomelanocortin neurons (GLP-1RKD?POMCcre). Chow-fed GLP-1RKD?Nkx2.1cre mice exhibited increased food intake and energy expenditure with no net effect on body weight. When fed a high-fat diet, these mice exhibited normal food intake but elevated energy expenditure, yielding reduced weight gain. None of these phenotypes were observed in GLP-1RKD?Sim1cre and GLP-1RKD?POMCcre mice. The acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA exendin-4 and liraglutide were preserved in all mouse lines. Chronic liraglutide treatment reduced body weight in chow-fed GLP-1RKD?Nkx2.1cre mice, but this effect was attenuated with high-fat diet feeding. In sum, classic homeostatic control regions are sufficient but not individually necessary for the effects of GLP-1RA on nutrient homeostasis.

SUBMITTER: Burmeister MA

PROVIDER: S-EPMC5248999 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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The Hypothalamic Glucagon-Like Peptide 1 Receptor Is Sufficient but Not Necessary for the Regulation of Energy Balance and Glucose Homeostasis in Mice.

Burmeister Melissa A MA Ayala Jennifer E JE Smouse Hannah H Landivar-Rocha Adriana A Brown Jacob D JD Drucker Daniel J DJ Stoffers Doris A DA Sandoval Darleen A DA Seeley Randy J RJ Ayala Julio E JE

Diabetes 20161201 2

Pharmacological activation of the hypothalamic glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) promotes weight loss and improves glucose tolerance. This demonstrates that the hypothalamic GLP-1R is sufficient but does not show whether it is necessary for the effects of exogenous GLP-1R agonists (GLP-1RA) or endogenous GLP-1 on these parameters. To address this, we crossed mice harboring floxed Glp1r alleles to mice expressing Nkx2.1-Cre to knock down Glp1r expression throughout the hypothalamu ...[more]

PMID: 27908915

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Project description:Wnt signalling and its downstream effectors are well known for their roles in embryogenesis and tumourigenesis, including the regulation of cell proliferation, survival and differentiation. In the nervous system, Wnt signalling has been described mainly during embryonic development, although accumulating evidence suggests that it also plays a major role in adult brain morphogenesis and function. Studies have predominantly concentrated on memory formation in the hippocampus, although recent data indicate that Wnt signalling is also critical for neuroendocrine control of the developed hypothalamus, a brain centre that is key in energy balance regulation and whose dysfunction is implicated in metabolic disorders such as type 2 diabetes and obesity. Based on scattered findings that report the presence of Wnt molecules in the tanycytes and ependymal cells lining the third ventricle and arcuate nucleus neurones of the hypothalamus, their potential importance in key regions of food intake and body weight regulation has been investigated in recent studies. The present review brings together current knowledge on Wnt signalling in the hypothalamus of adult animals and discusses the evidence suggesting a key role for members of the Wnt signalling family in glucose and energy balance regulation in the hypothalamus in diet-induced and genetically obese (leptin deficient) mice. Aspects of Wnt signalling in seasonal (photoperiod sensitive) rodents are also highlighted, given the recent evidence indicating that the Wnt pathway in the hypothalamus is not only regulated by diet and leptin, but also by photoperiod in seasonal animals, which is connected to natural adaptive changes in food intake and body weight. Thus, Wnt signalling appears to be critical as a modulator for normal functioning of the physiological state in the healthy adult brain, and is also crucial for normal glucose and energy homeostasis where its dysregulation can lead to a range of metabolic disorders.

Project description:The current study has investigated the hypothalamic gene expressions regulated by glucocorticoid (GC), key hormones in energy homeostasis. Using serial analysis of gene expression (SAGE) method, we have studied the effects of adrenalectomy (ADX) and GC on the transcriptomes of mouse hypothalamus. Approximately, 180 000 SAGE tags, which correspond to 50 000 tag species, were isolated from each group of intact or adrenalectomized mice, as well as 1, 3 and 24 hours after GC injection. ADX has upregulated diazepam binding inhibitor gene expression, while downregulating vomeronasal 1 receptor D4, genes involved in mitochondrial phosphorylation (cytochrome c oxidase 1 and NADH dehydrogenase 3), 3b-hydroxysteroid dehydrogenase-1, and prostaglandin D2 synthase. GC has increased the gene expression levels of dehydrogenase/reductase member 3, prostaglandin D2 synthase, solute carrier family 4 member 4, and five cytoskeletal proteins including myosin light chain phosphorylatable fast and troponin C2 fast. On the other hand, GC has reduced the mRNA levels of calmodilin 1 and expressed sequence tag similar to (EST) calmodilin 2, ATP synthase F0 subunit 6, and solute carrier family 4 member 3. Moreover, seven uncharacterized and 43 novel transcripts were modulated by ADX and GC. The current study has identified genes that may regulate hypothalamic systems governing energy balance in response to ADX and GC. Keywords: Hormone effect analysis Male C57BL6 mice were obtained from Charles River Laboratories (St. Constant, QC, Canada), at 12-14 weeks of age. Mice were housed in an air-conditioned room (19-25 degree) with controlled lighting from 07:15 to 19:15 h and were given free access to food (Lab Rodent Diet No. 5002) and water. One week prior to sampling of hypothalamus, adrenalectomy was performed in mice of all experimental groups (n = 12 per group). ADX mice received sodium chloride (0.9g/dl) in their drinking water after the surgery. GC (corticosterone, 0.1 mg per mouse) was subcutaneously injected to ADX mice and the hypothalamus was harvested at 1 hour (ADX + GC 1 h), 3 hours (ADX + GC 3 h) and 24 hours (ADX + GC 24 h) after the GC injection. ADX received an injection of vehicle solution (5% ethanol with 0.4% methocel A15LV premium) at 24 hours prior to sacrifice. All mice were killed between 08:30 and 12:30 by decapitation under isoflurane anesthesia. Brain was removed from the skull and the hypothalamus was immediately dissected, frozen in liquid nitrogen, pooled together for each group, and stored at -80 degree until RNA extraction.

Dataset Information

The Hypothalamic Glucagon-Like Peptide 1 Receptor Is Sufficient but Not Necessary for the Regulation of Energy Balance and Glucose Homeostasis in Mice.

Publications

The Hypothalamic Glucagon-Like Peptide 1 Receptor Is Sufficient but Not Necessary for the Regulation of Energy Balance and Glucose Homeostasis in Mice.

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