TY - JOUR
T1 - Glucagon-like peptide-1 regulates brown adipose tissue thermogenesis via the gut-brain axis in rats
AU - Krieger, Jean Philippe
AU - da Conceição, Ellen Paula Santos
AU - Sanchez-Watts, Graciela
AU - Arnold, Myrtha
AU - Pettersen, Klaus G.
AU - Mohammed, Mazher
AU - Modica, Salvatore
AU - Lossel, Pius
AU - Morrison, Shaun F.
AU - Madden, Christopher J.
AU - Watts, Alan G.
AU - Langhans, Wolfgang
AU - Lee, Shin J.
N1 - Funding Information:
This work was supported by the Swiss National Science Foundation, Marie Heim-Vögtlin Grant PMPDP3_151360 (to S. J. Lee), Eidgenössische Tech-nische Hochschule Zürich research Grant 47 12-2 (to W. Langhans and S. J. Lee), NIH Grant R01-NS-091066 (to S. F. Morrison), and NIH Grant NS-029728 (to A.G. Watts).
Funding Information:
We thank C. Liberini and A. Malbon (University of Zurich) for technical and scientific help with laser capture microdissection; T. Lutz and C. Boyle (University of Zurich) for support and advice related to indirect calorimetry measurements; R. Clara, S. Fedele, N. Jejelava, N. Weissfeld, and S. Kaufman (Eidgenössische Technische Hochschule Zürich) for precious help during animal experiments; R. Burcelin (INSERM Toulouse) and M. Hayes (University of Pennsylvania) for scientific advice during study preparation; A. Jokiaho (University of Southern California) for technical assistance with the herpes simplex virus tracing; and Dr. L. Enquist at the Center for Neuroanatomy with Neurotropic Viruses, University of Princeton (NIH P40-OD-010996) for providing pseudorabies virus (PRV)-263, PRV-152, and HSV-1 H129-772. This work was supported by the Swiss National Science Foundation, Marie Heim-Vögtlin Grant PMPDP3_151360 (to S. J. Lee), Eidgenössische Technische Hochschule Zürich research Grant 47 12-2 (to W. Langhans and S. J. Lee), NIH Grant R01-NS-091066 (to S. F. Morrison), and NIH Grant NS-029728 (to A.G. Watts).
Publisher Copyright:
© 2018 American Physiological Society. All rights reserved.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2018/10
Y1 - 2018/10
N2 - 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.
AB - 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.
KW - Energy expenditure
KW - Exendin-4
KW - High-fat diet
KW - Obesity
KW - Vagal afferent neurons
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UR - http://www.scopus.com/inward/citedby.url?scp=85053663787&partnerID=8YFLogxK
U2 - 10.1152/ajpregu.00068.2018
DO - 10.1152/ajpregu.00068.2018
M3 - Article
C2 - 29847161
AN - SCOPUS:85053663787
VL - 315
SP - R708-R720
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 0363-6119
IS - 4
ER -