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

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.

journal_name

Mol Metab

journal_title

Molecular metabolism

authors

Lee SJ,Sanchez-Watts G,Krieger JP,Pignalosa A,Norell PN,Cortella A,Pettersen KG,Vrdoljak D,Hayes MR,Kanoski SE,Langhans W,Watts AG

doi

10.1016/j.molmet.2018.03.008

subject

Has Abstract

pub_date

2018-05-01 00:00:00

pages

33-46

issn

2212-8778

pii

S2212-8778(18)30143-1

journal_volume

11

pub_type

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