loss of dorsomedial hypothalamic glp-1 signaling reduces bat thermogenesis and increases adiposity

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ID: 230712
2018
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Abstract
Objective: Glucagon-like peptide-1 (GLP-1) neurons in the hindbrain densely innervate the dorsomedial hypothalamus (DMH), a nucleus strongly implicated in body weight regulation and the sympathetic control of brown adipose tissue (BAT) thermogenesis. Therefore, DMH GLP-1 receptors (GLP-1R) are well placed to regulate energy balance by controlling sympathetic outflow and BAT function. Methods: We investigate this possibility in adult male rats by using direct administration of GLP-1 (0.5 ug) into the DMH, knocking down DMH GLP-1R mRNA with viral-mediated RNA interference, and by examining the neurochemical phenotype of GLP-1R expressing cells in the DMH using in situ hybridization. Results: GLP-1 administered into the DMH increased BAT thermogenesis and hepatic triglyceride (TG) mobilization. On the other hand, Glp1r knockdown (KD) in the DMH increased body weight gain and adiposity, with a concomitant reduction in energy expenditure (EE), BAT temperature, and uncoupling protein 1 (UCP1) expression. Moreover, DMH Glp1r KD induced hepatic steatosis, increased plasma TG, and elevated liver specific de-novo lipogenesis, effects that collectively contributed to insulin resistance. Interestingly, DMH Glp1r KD increased neuropeptide Y (NPY) mRNA expression in the DMH. GLP-1R mRNA in the DMH, however, was found in GABAergic not NPY neurons, consistent with a GLP-1R-dependent inhibition of NPY neurons that is mediated by local GABAergic neurons. Finally, DMH Glp1r KD attenuated the anorexigenic effects of the GLP-1R agonist exendin-4, highlighting an important role of DMH GLP-1R signaling in GLP-1-based therapies. Conclusions: Collectively, our data show that DMH GLP-1R signaling plays a key role for BAT thermogenesis and adiposity. Keywords: Neuropeptide, Hypothalamus, Sympathetic nerve, Adipose tissue, Obesity
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lee2018molecularloss Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Shin J. Lee, Graciela Sanchez-Watts, Jean-Philippe Krieger, Angelica Pignalosa, Puck N. Norell, Alyssa Cortella, Klaus G. Pettersen, Dubravka Vrdoljak, Matthew R. Hayes, Scott Kanoski, Wolfgang Langhans, Alan G. Watts
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Journal Small (Weinheim an der Bergstrasse, Germany)
Year 2018
DOI
DOI not found
URL
http://www.sciencedirect.com/science/article/pii/S2212877818301431
Keywords
internal medicine

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