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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Research Article Metabolism

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 3

Effect of Gpr21 deletion on BW gain, food intake, and glucose tolerance.

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Effect of Gpr21 deletion on BW gain, food intake, and glucose tolerance....
(A) BW gain and (B) weekly food intake of 12-week HFD-fed Gpr21 KO and WT littermates (n = 38–40 per group). (C) i.p. GTT (1 g/kg) on BW-matched Gpr21 KO and WT mice fed HFD for 11 weeks (n = 5–6 per group). (D) Insulin concentration at the indicated time points. (E–I) Hyperinsulinemic-euglycemic clamp study on Gpr21 KO and WT littermates (n = 6 WT, 12 Gpr21 KO, 6 Gpr21 KO BW-matched to WT). (E) GIR. (F) Basal HGP. (G) HGP suppression by insulin. (H) IS-GDR. (I) Insulin-induced FFA suppression. (J) EE in Gpr21 KO and WT littermates over a 24-hour period. (K) Average VO2 (ml/kg/h) and (L) average VCO2 in the light and dark cycles. (M) CBT of Gpr21 KO and WT mice in a 24-hour period, averaged across 3 days. (N) Average activity in the dark and light cycles. (O) q-PCR analysis of BAT expression of Prdm16, Pgc1α, and Ucp1. (P) BAT weight. (Q) q-PCR analysis of inflammatory gene expression in BAT. #P < 0.1 (NS), *P < 0.05 vs. WT, repeated-measures 2-way ANOVA (A–D), 2-way ANOVA (E–I), or Student’s t test (J–Q).