An FGF21-Adiponectin-Ceramide Axis Controls Energy Expenditure and Insulin Action in Mice

Abstract

SUMMARY FGF21, a member of the fibroblast growth factor (FGF) superfamily has recently emerged as a novel regulator of metabolism and energy utilization. However, the exact mechanism(s) whereby FGF21 mediates its actions have not been elucidated. There is considerable evidence that insulin resistance may arise from aberrant accumulation of intracellular lipids in insulin responsive tissues due to lipotoxicity. In particular the sphingolipid ceramide has been implicated in this process. Here, we show that FGF21 rapidly and robustly stimulates adiponectin secretion in rodents, while diminishing accumulation of ceramides in obese animals. Importantly, adiponectin knockout mice are refractory to changes in energy expenditure and ceramide-lowering effects evoked by FGF21 administration. Moreover, FGF21 lowers blood glucose levels and enhances insulin sensitivity in diabetic Lepob/ob mice and diet-induced obese (DIO) mice, only when adiponectin is functionally present. Collectively, these data suggest that FGF21 is a potent regulator of adiponectin secretion, and that FGF21 critically depends on adiponectin to exert its glycemic and insulin sensitizing effects.

Oncostatin M is a potential agent for the treatment of obesity and related metabolic disorders: a study in mice

“…Therefore, OSM seems to be a candidate for a powerful therapeutic agent without unfavourable side effects in the treatment of obesity-related metabolic diseases. Recently, it has also been reported that the metabolic effects of FGF21 are mediated by adiponectin (the so-called 'FGF21- [27,28]. In the present study, treatment with OSM did not induce an increase in serum adiponectin levels, suggesting that OSM exerts its metabolic effects independent of adiponectin.…”

Adiponectin as a tissue regenerating hormone: more than a metabolic function

“…Several studies report that T2 DM could affect the function of circulating ePC, by impairing migration [84,85], [15]; on mesoangioblasts by activating proliferation, cell motility, myogenesis, and inhibiting both apoptosis and anoikis [60]; on hemopoietic stem cells [71] and hippocampal neural stem cells by inducing cell proliferation [72]. In skeletal muscle, gAd promotes the differentiation of myoblasts into myotubes [40]. In the kidney, fAd acts by inhibiting apoptosis in podocytes and by supporting renal recovery [76].…”

“…Recent data report the involvement of a cross-talk between adiponectin and fibroblast growth factor 21 (FGF21) in the insulin-sensitizing effect of adiponectin. FGF21, a metabolic hormone that regulates glucose and lipid homeostasis and insulin sensitivity [39], enhances adiponectin secretion by adipocytes and increases circulating adiponectin in mice [40,41]. Interestingly, FGF21 decreases accumulation of ceramides in obese animals in an adiponectin-dependent fashion.…”

“…Interestingly, FGF21 decreases accumulation of ceramides in obese animals in an adiponectin-dependent fashion. Indeed, adiponectin-knockout (KO) mice are refractory to changes in energy expenditure and ceramide-lowering effects due to FGF21 administration [40], thus suggesting that FGF21-adiponectin cross-talk can have a key role in reducing the aberrant accumulation of lipids associated with insulin resistance.…”

Myokines in insulin resistance and type 2 diabetes

“…As summarised in Table 1, in vitro studies have shown that IL-6 increases myotube fatty acid oxidation and lipolysis via AMPK activation [32,33]. [46] No data available regarding endocrine metabolic effects of muscle-derived BDNF IL-6 ↑ GLUT4 translocation [19,20] ↑ Glucose uptake [15,19] ↑ Glycogen synthesis [18,20] ↑ Fatty acid oxidation [18][19][20] ↑ Lipolysis [32][33][34] Liver: ↑ Glucose production [23] Intestine: ↑ GLP-1 secretion of L cells [52] Pancreas: ↑ Beta cell proliferation [52] ↑ GLP-1 secretion of alpha cells [52] ↑ Proliferation and ↓ apoptosis of alpha cells [51] IL-13 ↑ Glucose uptake [28] ↑ Glucose oxidation [28] ↑ Glycogen synthesis [28] Liver: ↓ Glucose production [29] IL-15 ↑ Fatty acid oxidation [43] Adipose tissue: ↓ Lipid accumulation [44,45] ↑ Adiponectin secretion [44] Irisin No data available Adipose tissue: ↑ White to brown shift [98,111] No effect on browning [100] FGF21 ↑ Glucose uptake [99,136] Adipose tissue: ↑ White to brown shift [99] ↑ Glucose uptake [99] ↑ Adiponectin secretion [127,128] Liver: ↑ Fatty acid oxidation [137] ↑ Gluconeogenesis [137] Recently, a study using isolated mouse muscle reported that IL-6...…”