Paternal Gastric Bypass Surgery Confers Protection from Metabolic Syndrome and Hepatic Steatosis in Offspring Mice

Bariatric surgery is increasingly recognized as a potent approach for obesity and T2D. While bariatric surgery in females yields variable effects on offspring, the impact of bariatric surgery in males on metabolism of their offspring is unknown. To determine whether paternal RYGB could induce intergenerational effects, male C57BL/6 mice with Roux-en-Y gastric bypass 5 months earlier (RYGB, n=4) or weight/age-matched controls (CON, n=5) were bred with healthy females of the same strain; 3 pregnancies were achieved by RYGB and 6 by CON males. Birth weight of offspring from RYGB or CON fathers did not differ. Seven offspring (2 litters) of RYGB fathers and 12 (2 litters) of CON fathers survived to weaning. On chow diet, male offspring of RYGB fathers reduced weight gain over time (p<0.05 vs. CON) but there was no significant difference in insulin sensitivity or glucose tolerance at 3 months of age. At 6 months of age, male offspring of RYGB fathers had significantly lower fasting glucose and improved oral glucose tolerance (17% lower AUC, p<0.05). When fed a 45% high-fat diet (HFD) for 15 weeks, RYGB offspring had significantly lower weight gain than control offspring, with lower body weight (37±5.7g vs. 51±1.1g), and reduced fat percentage (36±6.8 vs. 48±1.1%), in turn potentially linked to reduced food intake. Moreover, RYGB offspring had lower fasting glucose, improved insulin sensitivity (intraperitoneal insulin tolerance), and increased respiratory exchange ratio in fed state. In addition, HFD-fed RYGB offspring had dramatic improvement in hepatic steatosis, with 70% of RYGB offspring having no steatosis, as compared with 100% of CON offspring with severe steatosis (p<0.0001). In conclusion, RYGB surgery in fathers prior to breeding can provide protection against metabolic syndrome and hepatic steatosis in offspring, and suggests that interventions to improve the health of fathers could interrupt intergenerational cycles of obesity and diabetes risk. Disclosure Y. Yuchi: None. Z. Hao: None. T. Takagi: None. H. Berthoud: None. M.E. Patti: Consultant; Self; Eiger BioPharmaceuticals. Research Support; Self; Dexcom, Inc., Janssen Pharmaceuticals, Inc., MedImmune, Xeris Pharmaceuticals, Inc. Funding The Medical Foundation; National Institutes of Health (DK047348)