One important question is whether the treatment of metabolic abnormalities accompanying obesity and diabetes and the relief of stress in diverse tissues occur through the same or overlapping adipocyte signals controlled by FGF21 (Table 1). The uncoupling of lipolysis and lipogenesis by FGF21-FGFR1-KLB directly in adipocytes and indirectly in hepatocytes together with FGF21-stimulated “browning” of fat and thermogenesis have been suggested to create a state of futile cycling and enhanced energy expenditure that causes overall reduction of body weight and systemic lipids in the obese (1, 29, 40, 46, 49). Under the life-threatening stress of prolonged starvation, this same FGF21-FGFR1-KLB mediated uncoupling of overall lipid and carbohydrate metabolism may serve to stretch out lipid reserves for brain fuels to preserve consciousness and reduce neural stress for as long as possible until feeding resumes (9, 46). FGF21-elicited adipocyte signals appear to commonly alleviate the extent of hepatic steatosis under the opposite metabolic extremes of obesity and starvation, and the muscular metabolic stress associated with autophagic defects and mitochondrial respiratory dysfunction.
