Circadian and Metabolic Control of Macrophage Activation in Obesity

Abstract

Macrophage inflammatory status governs inflammatory responses in metabolic tissues including adipose and liver tissues, and critically contributes to the development of diet-induced obesity and systemic insulin resistance. Therefore, regulating macrophage proinflammatory or anti-inflammatory activation can help control the diet-induced inflammation in adipose tissue and systemic insulin resistance. To better understand the control of macrophage activation status, circadian clockworks and PFKFB3 were investigated in the context of diet-induced inflammation and insulin resistance.

Through in vivo studies of bone marrow-transplanted mice fed with high fat diet (HFD) for 12 weeks, and in vitro studies on bone marrow-derived macrophage (BMDM) and co-cultures of BMDM and adipocytes, the present study demonstrated that disruption of circadian genes Period1 and Period2 in macrophages increases their proinflammatory activation, and exacerbates diet-induced inflammation and insulin resistance. Through similar research methods, this research showed that PFKFB3 disruption in macrophages exacerbates diet-induced adipose tissue inflammation and insulin resistance. Taken together, both the circadian clock and PFKFB3 were shown to be key regulators of macrophage activation, evidenced by that either dysregulation of circadian clock or disruption of PFKFB3 contributes to the physiological cascade by which diet-induced obesity triggers macrophage proinflammatory activation, adipose tissue inflammation, and insulin resistance.