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

• Main Authors: Shin J. Lee (Author), Graciela Sanchez-Watts (Author), Jean-Philippe Krieger (Author), Angelica Pignalosa (Author), Puck N. Norell (Author), Alyssa Cortella (Author), Klaus G. Pettersen (Author), Dubravka Vrdoljak (Author), Matthew R. Hayes (Author), Scott Kanoski (Author), Wolfgang Langhans (Author), Alan G. Watts (Author)
• Format: Book
• Published: Elsevier, 2018-05-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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

Item Description

2212-8778
10.1016/j.molmet.2018.03.008