Glucagon-like peptide-1 regulates brown adipose tissue thermogenesis via the gut-brain axis in rats

May 31, 2018American journal of physiology. Regulatory, integrative and comparative physiology

Glucagon-like peptide-1 controls heat production in brown fat through gut-brain communication in rats

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Abstract

GLP-1 signaling in vagal afferent neurons is associated with altered energy expenditure and thermogenesis in brown adipose tissue.

Vagal afferent neurons (VANs) are involved in regulating brown adipose tissue (BAT) thermogenesis and energy expenditure.
Knocking down the GLP-1 receptor in VANs reduced the effectiveness of the GLP-1 receptor agonist exendin-4 on energy expenditure and BAT thermogenesis.
VAN GLP-1 receptor knockdown resulted in increased energy expenditure and BAT activity, along with reduced body weight gain and improved insulin sensitivity during high-fat diet feeding.
Neuronal tracing indicates that VANs expressing GLP-1 receptors are connected to brain areas that regulate sympathetic activity in BAT.
The findings suggest that intestinal GLP-1 may contribute to metabolic syndrome associated with high-fat diets through its effects on VANs.

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Endogenous intestinal glucagon-like peptide-1 (GLP-1) controls satiation and glucose metabolism via vagal afferent neurons (VANs). Recently, VANs have received increasing attention for their role in brown adipose tissue (BAT) thermogenesis. It is, however, unclear whether VAN GLP-1 receptor (GLP-1R) signaling affects BAT thermogenesis and energy expenditure (EE) and whether this VAN mechanism contributes to energy balance. First, we tested the effect of the GLP-1R agonist exendin-4 (Ex4, 0.3 μg/kg ip) on EE and BAT thermogenesis and whether these effects require VAN GLP-1R signaling using a rat model with a selective Glp1r knockdown (kd) in VANs. Second, we examined the role of VAN GLP-1R in energy balance during chronic high-fat diet (HFD) feeding in VAN Glp1r kd rats. Finally, we used viral transsynaptic tracers to identify the possible neuronal substrates of such a gut-BAT interaction. VAN Glp1r kd attenuated the acute suppressive effects of Ex4 on EE and BAT thermogenesis. Consistent with this finding, the VAN Glp1r kd increased EE and BAT activity, diminished body weight gain, and improved insulin sensitivity compared with HFD-fed controls. Anterograde transsynaptic viral tracing of VANs infected major hypothalamic and hindbrain areas involved in BAT sympathetic regulation. Moreover, retrograde tracing from BAT combined with laser capture microdissection revealed that a population of VANs expressing Glp1r is synaptically connected to the BAT. Our findings reveal a novel role of VAN GLP-1R signaling in the regulation of EE and BAT thermogenesis and imply that through this gut-brain-BAT connection, intestinal GLP-1 plays a role in HFD-induced metabolic syndrome.

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Glucagon-like peptide-1 regulates brown adipose tissue thermogenesis via the gut-brain axis in rats

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