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

Abstract

ObjectiveGlucagon-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.MethodsWe 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.ResultsGLP-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.ConclusionsCollectively, our data show that DMH GLP-1R signaling plays a key role for BAT thermogenesis and adiposity.

Effect of central JAZF1 on glucose production is regulated by the PI3K‐Akt‐AMPK pathway

“…The decrease in food intake may be due to activation of the PI3K/Akt pathway to inhibit the expression of orexigenic neurons, as we and others have previously shown 30‐32 . Moreover, the hypothalamus has been shown to modulate energy balance and BAT thermogenesis by controlling sympathetic outflow 33 . Therefore, increased oxygen consumption, including fatty acid oxidation (FAO) and energy expenditure, in MBH Ad‐ JAZF1 ‐treated rats indicates an important link between MBH JAZF1 projections and the sympathetic regulation of BAT thermogenesis and energy balance 34 .…”

Preproglucagon Neurons in the Nucleus of the Solitary Tract Are the Main Source of Brain GLP-1, Mediate Stress-Induced Hypophagia, and Limit Unusually Large Intakes of Food

“…The current study adds to the significance of these projections by demonstrating a high GLP-1 content in spinal cord, the majority of which is supplied by NTS PPG neurons. This suggests a significant physiological role for spinal GLP-1 release, an intriguing path for future research considering the role of GLP-1 in sympathetic outflow (30–33).…”

Chronic Suppression of Glucagon-Like Peptide-1 Receptor (GLP1R) mRNA Translation in the Rat Bed Nucleus of the Stria Terminalis Reduces Anxiety-Like Behavior and Stress-Induced Hypophagia, But Prolongs Stress-Induced Elevation of Plasma Corticosterone

“…used to reduce translatable GLP1R mRNA in different brain regions (Schmidt et al, 2016;Alhadeff et al, 2017;Tuesta et al, 2017;Lee et al, 2018;Ló pez-Ferreras et al, 2018). We refer to this as "GLP1R knockdown," because we assume that reduced levels of detectable GLP1R mRNA are accompanied by reduced levels of functional GLP1R protein; however, the current lack of specific antibodies with which to detect GLP1R protein via immunocytochemistry or Western blot precludes a direct test of this assumption.…”