Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on regulating glucose and lipid homeostasis and insulin sensitivity. However, the mechanisms underlying the metabolic actions of FGF21 remain unknown. Here we show that the insulin-sensitizing adipokine adiponectin is a downstream effector of FGF21. Treatments with FGF21 enhanced both expression and secretion of adiponectin in adipocytes, thereby increasing serum levels of adiponectin in mice. Adiponectin knockout mice were refractory to several therapeutic benefits of FGF21, including alleviation of obesity-associated hyperglycemia, hypertriglyceridemia, insulin resistance, and hepatic steatosis. Furthermore, the effects of FGF21 on attenuation of obesity-induced impairment in insulin signaling in liver and skeletal muscle were abrogated in adiponectin knockout mice, whereas FGF21-mediated activation of ERK1/ERK2 in adipose tissues remained unaffected. Therefore, adiponectin couples FGF21 actions in local adipocytes to liver and skeletal muscle, thereby mediating the systemic effects of FGF21 on energy metabolism and insulin sensitivity.

Background-Altered composition of the gut microbiota is involved in both the onset and progression of obesity and diabetes mellitus. However, the link between gut microbiota and obesity-related cardiovascular complications has not been explored. The present study was designed to investigate the role of Akkermansia muciniphila, a mucin-degrading bacterium with beneficial effects on metabolism, in the pathogenesis of atherosclerosis in apolipoprotein E-deficient (Apoe −/− ) mice. Methods and Results-Apoe−/− mice on normal chow diet or a Western diet were treated with A muciniphila by daily oral gavage for 8 weeks, followed by histological evaluations of atherosclerotic lesion in aorta. Real-time polymerase chain reaction analysis demonstrated that the fecal abundance of A muciniphila was significantly reduced by Western diet. Replenishment with A muciniphila reversed Western diet-induced exacerbation of atherosclerotic lesion formation without affecting hypercholesterolemia. A muciniphila prevented Western diet-induced inflammation in both the circulation and local atherosclerotic lesion, as evidenced by reduced macrophage infiltration and expression of proinflammatory cytokines and chemokines. These changes were accompanied by a marked attenuation in metabolic endotoxemia. A muciniphila-mediated reduction in circulating endotoxin level could be attributed to the induction of intestinal expression of the tight junction proteins (zona occuldens protein-1 and occludin), thereby reversing Western diet-induced increases in gut permeability. Long-term infusion of endotoxin to Apoe −/− mice reversed the protective effect of A muciniphila against atherosclerosis. Conclusion-A muciniphila Li et al Antiatherosclerotic Role of A muciniphila 2435into the circulation, resulting in metabolic endotoxemia, and the elevated endotoxins in circulation exacerbate hepatic insulin resistance and promote weight gain. 9 Although associations between alterations in gut microbiota and many chronic diseases have been observed, it remains unclear whether such changes are the cause or the consequence of the pathologies.Atherosclerosis, the main contributor to cardiovascular mortality, is a chronic inflammatory disease. 10 Bacterial infection has been proposed as one of the triggers of inflammation in atherosclerosis. 11,12 For example, Chlamydia pneumonia is present in atherosclerotic lesions of patients with previous exposure, and infection with this bacterium exacerbates atherosclerosis in animals. 11,12 Bacterial DNA has been detected in atherosclerotic lesions, and the pyrosequencing result reveals that the bacteria in lesions are derived from gut and oral cavity, 13 suggesting a possible involvement of gut microbiota in the development of the disease. However, the germ-free atherogenic mice lacking apolipoprotein E (Apoe −/ ) mice, which are without the colonization of gut microbiota, show a worsening of atherosclerotic lesions after being fed a high-cholesterol diet compared with the conventionally raised mice, and antibiotic ther...

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