G protein-coupled receptor 21 deletion improves insulin sensitivity in diet-induced obese mice

Olivia Osborn, Dayoung Oh, Joanne McNelis, Manuel Sanchez-Alavez, Saswata Talukdar, Min Lu, Ping Ping 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

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2444-2453
Number of pages10
JournalJournal of Clinical Investigation
Issue number7
StatePublished - Jul 2 2012

ASJC Scopus subject areas

  • Medicine(all)


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