FGF21 in obesity and cancer: New insights

• Published in: Cancer letters 2021-02, Vol.499, p.5-13
• Main Authors: Lu, Weiqin, Li, Xiaokun, Luo, Yongde
• Format: Article
• Language: English
• Subjects: Acinar cells; Adenocarcinoma; Adipose tissue; Adipose Tissue - metabolism; Animals; Appetite; Autocrine Communication; Autocrine signalling; Carcinoma, Hepatocellular - etiology; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - prevention & control; Carcinoma, Pancreatic Ductal - etiology; Carcinoma, Pancreatic Ductal - pathology; Carcinoma, Pancreatic Ductal - prevention & control; Cell growth; Cell Proliferation; Diabetes; Disease Models, Animal; Energy expenditure; Energy Metabolism; Fatty acids; Fatty liver; Fatty Liver - etiology; Fatty Liver - pathology; Fibroblast growth factor receptor 1; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Glucagon; Glucose; Heparin; Hepatitis; Hepatocellular carcinoma; Homeostasis; Humans; Hyperglycemia; Hypothalamus; Hypothalamus - metabolism; Inflammation; Insulin; Insulin resistance; Klotho Proteins; Lipid Metabolism; Lipolysis; Liver; Liver - pathology; Liver cancer; Liver Neoplasms - etiology; Liver Neoplasms - pathology; Liver Neoplasms - prevention & control; Malignancy; Membrane Proteins - metabolism; Metabolic disorders; Mice; Mice, Transgenic; Mitochondria; Obesity; Obesity - complications; Obesity - metabolism; Obesity - pathology; Oncogenic KRAS; Oxidation; Pancreas; Pancreas - pathology; Pancreatic cancer; Pancreatic Neoplasms - etiology; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - prevention & control; Pancreatitis; Paracrine Communication; Paracrine signalling; Physiology; Protective Factors; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Roles; Signal Transduction
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2020.11.026

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. •FGF21 is a novel regulator of metabolic homeostasis with potent anti-obesity effect.•Oncogenic KRAS silences FGF21 gene expression to promote obesity-associated pancreatic cancer.•FGF21 loss concurs with the progression of fatty liver disease to hepatocellular carcinoma.•FGF21 signal pathway creates a barrier to metaflammation and tumorigenesis.•FGF21 may represent a therapeutic opportunity for cancers associated with metabolic abnormalities.