G protein–coupled receptor 21 deletion improves insulin sensitivity in diet-induced obese mice
Olivia Osborn, … , Tamas Bartfai, Jerrold M. Olefsky
Olivia Osborn, … , Tamas Bartfai, Jerrold M. Olefsky
Published June 1, 2012
Citation Information: J Clin Invest. 2012;122(7):2444-2453. https://doi.org/10.1172/JCI61953.
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G protein–coupled receptor 21 deletion improves insulin sensitivity in diet-induced obese mice

Abstract

Obesity-induced inflammation is a key component of systemic insulin resistance, which is a hallmark of type 2 diabetes. A major driver of this inflammation/insulin resistance syndrome is the accumulation of proinflammatory macrophages in adipose tissue and liver. We found that the orphan GPCR Gpr21 was highly expressed in the hypothalamus and macrophages of mice and that whole-body KO of this receptor led to a robust improvement in glucose tolerance and systemic insulin sensitivity and a modest lean phenotype. The improvement in insulin sensitivity in the high-fat diet–fed (HFD-fed) Gpr21 KO mouse was traced to a marked reduction in tissue inflammation caused by decreased chemotaxis of Gpr21 KO macrophages into adipose tissue and liver. Furthermore, mice lacking macrophage expression of Gpr21 were protected from HFD-induced inflammation and displayed improved insulin sensitivity. Results of in vitro chemotaxis studies in human monocytes suggested that the defect in chemotaxis observed ex vivo and in vivo in mice is also translatable to humans. Cumulatively, our data indicate that GPR21 has a critical function in coordinating macrophage proinflammatory activity in the context of obesity-induced insulin resistance.

Authors

Olivia Osborn, Da Young Oh, Joanne McNelis, Manuel Sanchez-Alavez, Saswata Talukdar, Min Lu, PingPing Li, Lucinda Thiede, Hidetaka Morinaga, Jane J. Kim, Jan Heinrichsdorff, Sarah Nalbandian, Jachelle M. Ofrecio, Miriam Scadeng, Simon Schenk, John Hadcock, Tamas Bartfai, Jerrold M. Olefsky

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Figure 5

Decreased macrophages in adipose tissue of Gpr21 KO mice.

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Decreased macrophages in adipose tissue of Gpr21 KO mice. (A) Confocal...
(A) Confocal merged images from epididymal fat pads of HFD-fed Gpr21 KO and WT mice costained with anti-F4/80 (cyan) and anti–caveolin-1 (blue) antibodies. Original magnification, ×200. (B) Number of crown-like structures (CLSs) per field in adipose tissue sections. (C) MCP-1 protein level in plasma of BW-matched HFD-fed mice. (D) FACS analysis of M1-like and M2-like ATM subsets in stromal vascular cells (SVCs). (E) Migratory capacity of i.p. macrophages, as measured by in vitro transwell chemotaxis assay using CM from 3T3L1 adipocytes, MCP-1 (100 ng/ml), or LTB4 (10 nM). (F) Gpr21 KO macrophage exhibited dysfunctional cytoskeletal organization. i.p. macrophages were treated with LPS (10 ng/ml) or MCP-1 (100 ng/ml) for 10 minutes, and phalloidin–Alexa Fluor 488 was used to stain F-actin. Scale bar: 50 μm. (G) Migratory capacity of human U-937 monocytes after human GPR21 was knocked down by RNAi, measured using an in vitro transwell chemotaxis assay. (H and I) Migratory capacity of Gpr21 macrophages in vivo to eWAT (H) and liver (I), assessed by PKH26-labeled monocytes. Data are mean ± SEM of 3 independent experiments in triplicate. #P < 0.1 (NS), *P < 0.05 vs. WT. All images are representative of results from 3 independent experiments.