Journal
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY
Volume 315, Issue 4, Pages R708-R720Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpregu.00068.2018
Keywords
vagal afferent neurons; exendin-4; high-fat diet; energy expenditure; obesity
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Funding
- Swiss National Science Foundation
- Marie Heim-Vogtlin Grant [PMPDP3_151360]
- Eidgenossische Technische Hochschule Zurich [47 12-2]
- NIH [R01-NS-091066, NS-029728]
- Swiss National Science Foundation (SNF) [PMPDP3_151360] Funding Source: Swiss National Science Foundation (SNF)
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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 xg/kg ip) on EE and BAT thermogenesis and whether these effects require VAN GLP-1R signaling using a rat model with a selective Glplr 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 Glp 1r kd rats. Finally, we used viral transsynaptic tracers to identify the possible neuronal substrates of such a gut-BAT interaction. VAN Glp 1r kd attenuated the acute suppressive effects of Ex4 on EE and BAT thermogenesis. Consistent with this finding, the VAN Glp 1r kd increased EE and BAT activity, diminished body weight gain, and improved insulin sensitivity compared with IIFD-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 Glp 1r 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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