The endocrine
hormone fibroblast growth factor 21 (
FGF21) is induced in the adaptive response to nutrient deprivation, where it serves to regulate the integrated response to fasting via its primary receptor complex,
FGF receptor 1 coupled with the cofactor β-klotho (KLB) in target tissues. Curiously, endogenous
FGF21 levels are also elevated in preclinical models of
obesity and in obese/diabetic individuals. In addition to higher
FGF21 levels, reduced KLB expression in liver and adipose tissue has been noted in these same individuals, suggesting that
obesity may represent an
FGF21 resistant state. To explore the contribution of tissue-specific KLB levels to endogenous
FGF21 activity, in both fasting and high-fat diet feeding conditions, we generated animals overexpressing KLB in liver (LKLBOE) or adipose (ATKLBOE). Supportive of tissue-specific partitioning of
FGF21 action, after chronic high-fat feeding, ATKLBOE mice gained significantly less weight than WT. Reduced
weight gain was associated with elevated caloric expenditure, accompanied by a reduced respiratory exchange ratio and lower plasma
free fatty acids levels, suggestive of augmented lipid metabolism. In contrast, LKLBOE had no effect on
body weight but did reduce plasma
cholesterol. The metabolic response to fasting was enhanced in LKLBOE mice, evidenced by increased
ketone production, whereas no changes in this were noted in ATKLBOE mice. Taken together, these data provide further support that specific effects of
FGF21 are mediated via engagement of distinct target organs. Furthermore, enhancing KLB expression in adipose may sensitize to endogenous
FGF21, thus representing a novel strategy to combat
metabolic disease.