The endocrine
FGF21 was discovered as a novel metabolic regulator in 2005 with new functions bifurcating from the canonic
heparin-binding FGFs that directly promote cell proliferation and growth independent of a co-receptor. Early studies have demonstrated that
FGF21 is a stress sensor in the liver and possibly, several other endocrine and metabolic tissues. Hepatic
FGF21 signals via endocrine routes to quench episodes of metabolic derangements, promoting metabolic homeostasis. The convergence of mouse and human studies shows that
FGF21 promotes
lipid catabolism, including lipolysis,
fatty acid oxidation, mitochondrial oxidative activity, and thermogenic energy dissipation, rather than directly regulating
insulin and appetite. The white and brown adipose tissues and, to some extent, the hypothalamus, all of which host a transmembrane receptor binary complex of FGFR1 and co-receptor KLB, are considered the essential tissue and molecular targets of hepatic or pharmacological
FGF21. On the other hand, a growing body of work has revealed that pancreatic acinar cells form a constitutive high-production site for
FGF21, which then acts in an autocrine or paracrine mode. Beyond regulation of macronutrient metabolism and physiological energy expenditure,
FGF21 appears to function in forestalling the development of fatty pancreas, steato-
pancreatitis,
fatty liver, and steato-
hepatitis, thereby preventing the development of advanced pathologies such as pancreatic ductal
adenocarcinoma or
hepatocellular carcinoma. This review is intended to provide updates on these new discoveries that illuminate the protective roles of FGF21-FGFR1-KLB signal pathway in metabolic anomalies-associated severe tissue damage and
malignancy, and to inform potential new preventive or therapeutic strategies for
obesity-inflicted
cancer patients via reducing metabolic risks and
inflammation.