Roux-en-Y gastric bypass surgery is effective in fibroblast growth factor-21 deficient mice

OBJECTIVE: The mechanisms by which bariatric surgeries so effectively and lastingly reduce body weight and normalize metabolic dysfunction are not well understood. Fibroblast growth fator-21 (FGF21) is a key regulator of metabolism and is currently considered for treatment of obesity. Although elevated by acute food deprivation, it is downregulated after weight loss induced by chronic calorie restriction but not after Roux-en-Y gastric bypass surgery. Therefore, the goal of the present study was to assess the role of FGF21-signaling in the beneficial effects of Roux-en-Y gastric bypass surgery (RYGB). METHODS: High-fat diet-induced obese FGF21-deficient (FGF21(−/−)) and wildtype (WT) mice were subjected to RYGB, sham surgery, or caloric restriction to match body weight of RYGB mice. Body weight, body composition, food intake, energy expenditure, glucose tolerance, and insulin sensitivity, as well as plasma levels and hepatic mRNA expression of FGF21 were measured. RESULTS: Hepatic expression and plasma levels of FGF21 are higher after RYGB compared with similar weight loss induced by caloric restriction, suggesting that elevated FGF21 might play a role in preventing increased hunger and weight regain after RYGB. However, although the body weight differential between RYGB and sham surgery was significantly reduced in FGF21(−/−) mice, RYGB induced similarly sustained body weight and fat mass loss, initial reduction of food intake, increased energy expenditure, and improvements in glycemic control in FGF21(−/−) and WT mice. CONCLUSIONS: FGF21 signaling is not a critical single factor for the beneficial metabolic effects of RYGB. This may open up the possibility to use FGF21 as adjuvant therapy in patients with ineffective bariatric surgeries.