Reduced food intake brings about an adaptive decrease in energy expenditure that contributes to the recidivism of obesity following weight loss. Insulin and leptin inhibit food intake through actions in the central nervous system that are partly mediated by FoxO1. We show that FoxO1 ablation in pro–opiomelanocortin (Pomc) neurons (Pomc–Foxo1−/−) reduces food intake without affecting energy expenditure. Analyses of hypothalamic neuropeptides in Pomc–Foxo1−/− mice reveal selective increases of α–Msh and COOH–cleaved β–endorphin, the products of Carboxypeptidase E (Cpe)–dependent processing of Pomc. We show that Cpe is decreased in diet–induced obesity, and that FoxO1 deletion offsets the decrease, protecting against weight gain. Moreover, moderate Cpe overexpression in the arcuate nucleus phenocopies features of the FoxO1 mutation. The dissociation of food intake from energy expenditure in Pomc–Foxo1−/− mice represents a model for therapeutic intervention in obesity, and raises the possibility of targeting Cpe to develop weight loss medications.

INTRODUCTION Gastric bypass surgery (GBP) leads to sustained weight loss and significant improvement in type 2 diabetes (T2DM). Bile acids (BAs), signaling molecules which influence glucose metabolism, are a potential mediator for the improvement in T2DM after GBP. This study sought to investigate the effect of GBP on BA levels and composition in individuals with T2DM. METHODS Plasma BA levels and composition and fibroblast growth factor (FGF)-19 levels were measured during fasting and in response to an oral glucose load before and at 1 month and 2 years post GBP in 13 severely obese women with T2DM. RESULTS A striking temporal change in BA levels and composition was observed after GBP. During the fasted state, BA concentrations were generally reduced at 1 month, but increased 2 years post GBP. Postprandial BA levels were unchanged 1 month post GBP, but an exaggerated postprandial peak was observed 2 years after the surgery. A significant increase in the 12α-hydroxylated/non12α-hydroxylated BA ratio during fasting and postprandially at 2 years, but not 1 month, post GBP was observed. Significant correlations between BAs vs FGF-19, body weight, the incretin effect and peptide YY (PYY) were also found. CONCLUSIONS This study provides evidence that GBP temporally modifies the concentration and composition of circulating BAs in individuals with T2DM, and suggests that BAs may be linked to the improvement in T2DM after GBP.

Severe obesity is a preeminent health care problem that impacts overall health and survival. The most effective treatment for severe obesity is bariatric surgery, an intervention that not only maintains long-term weight loss but also is associated with improvement or remission of several comorbidies including type 2 diabetes mellitus. Some weight loss surgeries modify the gastrointestinal anatomy and physiology, including the secretions and actions of gut peptides. This review describes how bariatric surgery alters the patterns of gastrointestinal motility, nutrient digestion and absorption, gut peptide release, bile acids and the gut microflora, and how these changes alter energy homeostasis and glucose metabolism.

The mechanisms responsible for the remarkable remission of type 2 diabetes after Roux-en-Y gastric bypass (RYGBP) are still puzzling. To elucidate the role of the gut, we compared β-cell function assessed during an oral glucose tolerance test (OGTT) and an isoglycemic intravenous glucose clamp (iso-IVGC) in: 1) 16 severely obese patients with type 2 diabetes, up to 3 years post-RYGBP; 2) 11 severely obese normal glucose-tolerant control subjects; and 3) 7 lean control subjects. Diabetes remission was observed after RYGBP. β-Cell function during the OGTT, significantly blunted prior to RYGBP, normalized to levels of both control groups after RYGBP. In contrast, during the iso-IVGC, β-cell function improved minimally and remained significantly impaired compared with lean control subjects up to 3 years post-RYGBP. Presurgery, β-cell function, weight loss, and glucagon-like peptide 1 response were all predictors of postsurgery β-cell function, although weight loss appeared to be the strongest predictor. These data show that β-cell dysfunction persists after RYGBP, even in patients in clinical diabetes remission. This impairment can be rescued by oral glucose stimulation, suggesting that RYGBP leads to an important gastrointestinal effect, critical for improved β-cell function after surgery.

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