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

Shin J Lee, Graciela Sanchez-Watts, Jean-Philippe Krieger, Angelica Pignalosa, Puck N Norell, Alyssa Cortella, Klaus G Pettersen, Dubravka Vrdoljak, Matthew R Hayes, Scott E Kanoski, Wolfgang Langhans, Alan G Watts, Shin J Lee, Graciela Sanchez-Watts, Jean-Philippe Krieger, Angelica Pignalosa, Puck N Norell, Alyssa Cortella, Klaus G Pettersen, Dubravka Vrdoljak, Matthew R Hayes, Scott E Kanoski, Wolfgang Langhans, Alan G Watts

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.

Keywords: Adipose tissue; Hypothalamus; Neuropeptide; Obesity; Sympathetic nerve.

Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.

Figures

Figure 1
Figure 1
DMH GLP-1R stimulation increases BAT thermogenesis and TG mobilization from liver. (A) Experimental protocol. (B, C) Representative infrared pictures of the interscapular area before and 4 h after Veh or GLP-1 (0.5 μg) injection into the DMH (n = 7–8; Two-way ANOVA; ***p < 0.0001). (D) Rectal temperature (n = 7/8; Two-way ANOVA; **p < 0.005). (E) Relative mRNA expression in the BAT: n = 7/7; Student t-tests; *p < 0.05 for ADRB3, CIDEA, PGC1α, PPARγ, ns (p > 0.05): UCP1, iodothyronine deiodinase 2 (DIO2), and FGF21. (F) Respiratory exchange ratio before (basal: 0–4 h after dark onset) and after (post injection:4–8 h after dark onset) Veh or GLP-1 injection into the DMH (n = 7/7; Two-way ANOVA; *p < 0.05). (G) Plasma TG levels (n = 7/8; Student t-test; *p < 0.05). (H) Relative mRNA expression in liver: n = 7/7; Student t-tests; *p < 0.05 for FAS. ns: sterol regulatory element-binding protein 1(SREBP1), HSL, ATGL, PEPCK1, and G6Pase. (I) Relative mRNA expression in the DMH: n = 7/7; Student t-test; *p < 0.05 for NPY. ns: CART and GLP-1R. Data are mean ± SEM.
Figure 2
Figure 2
DMH Glp1r KD increases BW gain and adiposity. (A) Illustration of AAV injection site and GFP infected cells in the DMH. (B) Relative GLP-1R mRNA expression in the DMH, ARC, and PVH (n = 6/8; Student t-tests; *p < 0.001 for DMH). (C) BW gain (as % of BW) of AAV-control and AAV-GLP-1R rats on standard chow diet for 11 weeks (n = 7/9; Student t-tests; *p < 0.05). (D) Lean and fat mass of AAV-control and AAV-GLP-1R rats (n = 7/9; Student t-tests; *p < 0.01). (E) Plasma leptin levels (n = 6/6; Student t-test; p = 0.09). (F) Daily food intake of AAV-control and AAV-GLP-1R rats for 22 days after surgery. (G) 4 h food intake after 24 h fasting (n = 7/9; Student t-test; *p < 0.001). (H) BW change after 24 h fasting (n = 7/9; Student t-test; *p < 0.05). Data are mean ± SEM.
Figure 3
Figure 3
DMH Glp1r KD decreases EE and BAT thermogenesis. (A) EE over 24 h in AAV-control and AAV-GLP-1R rats. (B) Average EE in dark and light phases (n = 7/9; Two-way ANOVA; *p < 0.0001). (C) RER over 24 h in AAV-control and AAV-GLP-1R rats. (D) Average RER in dark and light phases. (E) BAT temperature during the dark phase (n = 7/8; Student t-test; *p < 0.01). (F) Rectal temperature during the dark phase. (G) BAT temperate change 2 h after β-3 receptor agonist CL316243 injection (1 μg/kg i.p.; n = 3–5; Two-way ANOVA; *p < 0.005). (H) Representative pictures of H&E staining (Scale bar: 100 μm) and lipid area fraction in BAT of AAV-control and AAV-GLP-1R rats (n = 6/5; Student t-test; *p < 0.05). (I) Relative mRNA expression of thermogenic markers in BAT: n = 7/8; Student t-test; *p < 0.005 for UCP1; *p < 0.05 for PGC1α, PPARγ. ns: ADRB3. (J) Relative UCP1 protein expression in BAT (n = 5/7; Student t-test; *p < 0.01). Data are mean ± SEM.
Figure 4
Figure 4
DMH Glp1r KD rats develop hepatic steatosis and insulin resistance. (A) Plasma TG levels (n = 6/8; Student t-test; *p < 0.001). (B) Representative pictures of oil red O staining (Scale bar: 100 μm) and ORO area quantification in liver of AAV-control and AAV-GLP-1R rats (n = 5/5; Student t-test; p < 0.0005). (C) Relative mRNA expression in liver: n = 6/8; Student t-test; *p < 0.05 for FAS * p < 0.01 for PEPCK1; *p < 0.005 for G6Pase. p = 0.06 for ACC, ns: FGF21 and PGC1α. (D) Western blot for enzymes involved in do-novo lipogenesis: n = 7/8; Student t-test; *p < 0.05 for FAS and ACC. ns: pACC and pACC/ACC. (E) Relative mRNA expression in inguinal fat pad: n = 6/8; Student t-test; *p < 0.05 for FAS. ns: ATGL, HSL, and ACC. (F) Blood glucose profile during an IPGTT (2 g/kg glucose) in AAV-control and AAV-GLP-1R rats. The bar graph shows the area under curve. (G) Blood insulin profile during an IPGTT in AAV-control and AAV-GLP-1R rats. The bar graph shows the area under curve (n = 4/6; Student t-test; *p < 0.05). (H) Fasting plasma insulin levels in AAV-control and AAV-GLP-1R rats (n = 4/6; Student t-test; *p < 0.05). Data are mean ± SEM.
Figure 5
Figure 5
DMH GLP-1R signaling regulates NPY gene expression indirectly. (A) Relative mRNA expression in the DMH in AAV-control and AAV-GLP-1R rats: n = 6/9; Student t-test; *p < 0.0005 for NPY. ns: CART, LEPR, and CCKR. (B) Relative mRNA expression in the PVH. ns: CRH, TRH, TH (p = 0.07), and CART. (C) Relative mRNA expression in the ARC. ns: NPY, CART, POMC, and AgRP. (D) ISH/FISH for GLP-1R and NPY mRNA. Top (DMH) and bottom (ARC) panels: Left-GLP-1R mRNA (red), Middle-GLP-1R (red) and NPY (green), Right-co-localization in yellow. (E) ISH/FISH for GLP-1R and GAD-65 mRNA. Top (DMH) and bottom (ARC) panels: Left-GLP-1R mRNA (red), Middle-GLP-1R (red) and GAD-65 (green), Right-co-localization in yellow. Scale bar for all panels = 200 μm. Data are mean ± SEM.
Figure 6
Figure 6
Long term DMH Glp1r KD attenuates the anorexigenic response to Ex-4. (A) 24 h food intake after PBS or Ex-4 (1.0 μg/kg, i.p.) treatment in AAV-control and AAV-GLP-1R rats (n = 7/9; Two-way ANOVA; drug effect * p < 0.001, group effect #p < 0.05). (B) 24 h BW change after PBS or Ex-4 treatment in AAV-control and AAV-GLP-1R rats (n = 7/9; Two-way ANOVA; drug effect * p < 0.0005). (C) EE over 24 h after PBS or Ex-4 treatment in AAV-control and AAV-GLP-1R rats. (D) Average EE in dark phase after PBS or Ex-4 treatment in AAV-control and AAV-GLP-1R rats (n = 7/9; Two-way ANOVA; drug effect p < 0.01, group effect p < 0.0001, *p < 0.005). (E) RER over 24 h after PBS or Ex-4 treatment in AAV-control and AAV-GLP-1R rats. (F) Average RER in dark phase after PBS or Ex-4 treatment in AAV-control and AAV-GLP-1R rats (n = 7/9; Two-way ANOVA; drug effect p < 0.0005, *p < 0.001). Data are mean ± SEM.
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Source: PubMed

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