FGF21 decreases food intake and body weight in obese Göttingen minipigs

Abstract

Aims The aim of this study was to assess the effect of FGF21 on food intake, body weight, body composition, glucose homeostasis, bone mineral density (BMD), cortisol and growth hormone (GH) in obese minipigs. The pig is a unique model for studying FGF21 pharmacology as it does not express UCP1, unlike mice and humans. Methods Twelve obese Göttingen minipigs with a mean body weight of 91.6 ± 6.7 kg (mean ± SD) received subcutaneously either vehicle (n = 6) or recombinant human FGF21 (n = 6) once daily for 14 weeks (0.1 mg/kg for 9.5 weeks and 0.3 mg/kg for 4.5 weeks). Results Treatment of obese minipigs with FGF21 led to a 50% reduction in food intake and a body weight loss of, on average, 18 kg compared to the vehicle group after 14 weeks of dosing. Glucose tolerance and insulin sensitivity, evaluated by intravenous glucose tolerance test, were significantly improved in the FGF21 group compared to the vehicle group at the end of the study. The plasma cortisol profile was unaffected by FGF21, whereas a small decrease in peak GH values was observed in the FGF21‐treated animals after 7 to 9.5 weeks of treatment compared to the vehicle group. Whole‐body BMD was not affected by 13 weeks of FGF21 dosing. Conclusion Despite a lack of UCP‐1 in obese minipigs, FGF21 treatment induced a significant weight loss, primarily a result of reduction in food intake, with no adverse effect on BMD or plasma cortisol.

Maternal dietary resistant starch does not improve piglet’s gut and liver metabolism when challenged with a high fat diet

“…Another gene encoded for Fibroblast Growth Factor 21 (FGF21), and was more than 4-fold higher expressed in the HF animals. Subcutaneously injected FGF21 has been described to decrease food intake to 50% and therefore reduce body weight in minipigs [31]. FGF21 regulates triglyceride metabolism and it is shown that overexpression of FGF21 finally would lead to a decline in lipid accumulation [32].…”

Increased Expression of FGF-21 Negatively Affects Bone Homeostasis in Dystrophin/Utrophin Double Knockout Mice

“…Plasma FGF‐21 concentrations were negatively correlated with BMD in the femoral neck in Han Chinese adult population, in human immunodeficiency virus 1 (HIV‐1)‐infected patients, and in radial trabecular bone microarchitecture and strength in women with anorexia nervosa . However, others did not detect bone loss in rhFGF‐21–treated or AAV8‐hAAT‐FGF‐21 genetically engineered high‐fat diet–induced obesity mice, in high‐fat–fed obese monkeys and minipigs; and FGF‐21 knockout mice did not show high bone mass phenotype . An independent positive association between plasma FGF‐21 levels and BMD in 24 healthy young women and in postmenopausal women were also reported.…”

Circulating FGF21 Levels in Human Health and Metabolic Disease

“…Using human recombinant E.-coli-derived, i. e., non-glycosylated, FGF21, Xu et al reported a half-life of about 1.5-2 h after intravenous injection into C57BL/6 mice [159]. In other studies, half-lives of 20-30 min (CD-1, Swiss Webster mice, cynomolgus macaques [160,161]) and of 1.2 h (Sprague Dawley rats [162]) were measured with the identical protein, and recently a plasma half-life (T½) of 2h for native FGF21 in lean minipigs has been published [163]. Thus, it can be assumed that human (recombinant) FGF21 has a half-life of less than 2 h, while the in vivo stability of endogenous FGF21 is currently unknown.…”