FGF21 Is Increased by Inflammatory Stimuli and Protects Leptin-Deficient ob/ob Mice from the Toxicity of Sepsis

Abstract

The acute phase response (APR) produces marked alterations in lipid and carbohydrate metabolism including decreasing plasma ketone levels. Fibroblast growth factor 21 (FGF21) is a recently discovered hormone that regulates lipid and glucose metabolism and stimulates ketogenesis. Here we demonstrate that lipopolysaccharide (LPS), zymosan, and turpentine, which induce the APR, increase serum FGF21 levels 2-fold. Although LPS, zymosan, and turpentine decrease the hepatic expression of FGF21, they increase FGF21 expression in adipose tissue and muscle, suggesting that extrahepatic tissues account for the increase in serum FGF21. After LPS administration, the characteristic decrease in plasma ketone levels is accentuated in FGF21-/- mice, but this is not due to differences in expression of carnitine palmitoyltransferase 1α or hydroxymethyglutaryl-CoA synthase 2 in liver, because LPS induces similar decreases in the expression of these genes in FGF21-/- and control mice. However, in FGF21-/- mice, the ability of LPS to increase plasma free fatty acid levels is blunted. This failure to increase plasma free fatty acid could contribute to the accentuated decrease in plasma ketone levels because the transport of fatty acids from adipose tissue to liver provides the substrate for ketogenesis. Treatment with exogenous FGF21 reduced the number of animals that die and the rapidity of death after LPS administration in leptin-deficient ob/ob mice and to a lesser extent in control mice. FGF21 also protected from the toxic effects of cecal ligation and puncture-induced sepsis. Thus, FGF21 is a positive APR protein that protects animals from the toxic effects of LPS and sepsis.

Fibroblast growth factor 21 protects the heart from apoptosis in a diabetic mouse model via extracellular signal-regulated kinase 1/2-dependent signalling pathway

“…However, FGF21 is also expressed in other tissues such as the myocardium [11]. FGF21 was found to be an acute response protein to protect tissues from acute toxicity [12,13]. Additionally, the antiapoptotic effects of FGF21 on islet beta cells and endothelial cells were also reported [14,15].…”

Attenuated fibroblast growth factor 21 response to acute aerobic exercise in obese individuals

“…Circulating FGF21 concentrations are positively associated with body mass index (BMI) [7] and elevated in patients with T2D [8], potentially as a compensatory mechanism to mediate obesity related metabolic and inflammatory insult [9,10]. For example, plasma FGF21 concentrations as well as skeletal muscle mRNA expression were increased following 3e4 h of insulin infusion [10].…”

Serum Fibroblast Growth Factor-21 Levels Are Associated With Carotid Atherosclerosis Independent of Established Cardiovascular Risk Factors

“…Consistent with this observation, elevated serum FGF21 levels have also been demonstrated in mice after the administration of a variety of stimulants that induce an acute phase response. 21 On the basis of these observations, the elevation in serum FGF21 levels in subjects with carotid atherosclerosis may be part of a protective response to the vascular injury or inflammation in atherosclerosis, similar to the increased pancreatic FGF21 expression in ceruleininduced pancreatitis. …”