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

Apr 14, 2018Molecular metabolism

Reduced signaling in a brain area controlling energy balance lowers brown fat heat production and increases body fat

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Abstract

GLP-1 administered into the DMH increased brown adipose tissue thermogenesis and hepatic triglyceride mobilization.

Knocking down GLP-1 receptors in the DMH led to increased body weight gain and fat accumulation.
This receptor knockdown was associated with reduced energy expenditure, lower brown adipose tissue temperature, and decreased expression of uncoupling protein 1.
DMH GLP-1 receptor knockdown resulted in hepatic steatosis and increased plasma triglycerides, contributing to insulin resistance.
An increase in neuropeptide Y expression in the DMH was observed following GLP-1 receptor knockdown.
GLP-1 receptors in the DMH were identified in GABA-producing neurons, indicating a potential inhibitory effect on neuropeptide Y neurons.

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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.

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

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