Roux-en-Y gastric bypass (RYGB) leads to long-term weight loss and diabetes remission. Animal studies have shown that RYGB changes the physiology of energy regulation to favor a lower defended fat mass. To explore these effects, we developed a mouse model of enhanced response to dietary change, where RYGB abrogates the rapid obesogenic effects of re-exposure to a high-fat diet (HFD). HFD-induced obese mice that underwent RYGB- or Sham operation were fed chow for 9 weeks and switched back to HFD for 8 weeks. Glucose regulation was improved in RYGB animals independent of diet or body weight. During the first 2 days on HFD, Sham animals gained significant weight (1.8 g, p<0.05) due to a 10.6 kcal increase in energy intake (EI) compared to the chow period (p<0.05). In RYGB mice, weight and EI remained unchanged. By week 8 of HFD, Sham controls were 24% heavier than before surgery (p<0.05), while RYGB mice continued to maintain a lean weight. There was no difference in EI between groups, but RYGB mice exhibited 26% higher energy expenditure than Sham mice (p<0.05). Given the widespread changes in physiology in RYGB animals, we sought to identify differentially expressed (DE) genes in RYGB vs. Sham livers during the dynamic response to HFD. RNA-Seq showed that the number of DE genes after long-term HFD was 5.6 times larger than after 2 days (1,409 vs. 251, respectively), reflecting adaptation to a new metabolic state in Sham mice after chronic HFD. Differential expression of inflammatory, lipogenic, and cell cycle genes was substantially altered over time. These data suggest that the means by which RYGB modulates energy balance to resist the obesogenic effects of HFD is time-dependent. Further assessment of the molecular basis of this dynamic physiological response will provide important insight into the mechanisms most relevant to the therapeutic effects of RYGB and therefore guide development of less invasive therapies for metabolic disease.
M. Santoro: None. J. Brancale: None. J. Carmody Garrison: None. S. Machineni: Consultant; Self; Johnson & Johnson Services, Inc., Rhythm Pharmaceuticals Inc.. Other Relationship; Self; Novo Nordisk Inc.. S.A. Lajoie: None. L.M. Kaplan: None.