Loss of dorsomedial hypothalamic GLP-1 signaling reduces BAT thermogenesis and increases adiposity

• Published in: Molecular metabolism (Germany) 2018-05, Vol.11, p.33-46
• Main Authors: Lee, Shin J., Sanchez-Watts, Graciela, Krieger, Jean-Philippe, Pignalosa, Angelica, Norell, Puck N., Cortella, Alyssa, Pettersen, Klaus G., Vrdoljak, Dubravka, Hayes, Matthew R., Kanoski, Scott E., Langhans, Wolfgang, Watts, Alan G.
• Format: Article
• Language: English
• Subjects: Adipose tissue; Adipose Tissue, Brown - metabolism; Adiposity; Animals; Exenatide - metabolism; GABAergic Neurons - metabolism; Glucagon-Like Peptide 1 - metabolism; Glucagon-Like Peptide-1 Receptor - genetics; Glucagon-Like Peptide-1 Receptor - metabolism; Hypothalamus; Hypothalamus - metabolism; Insulin Resistance; Lipogenesis; Male; Neuropeptide; Neuropeptide Y - metabolism; Obesity; Original; Rats; Rats, Sprague-Dawley; Signal Transduction; Sympathetic nerve; Thermogenesis; Uncoupling Protein 1 - metabolism
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2018.03.008

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. 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. 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. Collectively, our data show that DMH GLP-1R signaling plays a key role for BAT thermogenesis and adiposity. •DMH GLP-1R stimulation acutely increases BAT thermogenesis.•DMH GLP-1R mRNA knockdown decreases EE and BAT thermogenesis.•DMH GLP-1R mRNA knockdown impairs lipid and glucose metabolism.•Reduced DMH GLP-1R signaling blunts the anorexigenic responses to Ex-4.•DMH GLP-1R signaling indirectly regulates NPY gene expression.