Metabolic benefits of gastric bypass surgery in the mouse: The role of fecal losses

Abstract

ObjectiveRoux-en-Y gastric surgery (RYGB) promotes a rapid and sustained weight loss and amelioration of glucose control in obese patients. A high number of molecular hypotheses were previously tested using duodenal-jejunal bypass (DJB) performed in various genetic models of mice with knockouts for various hormones or receptors. The data were globally negative or inconsistent. Therefore, the mechanisms remained elusive. Intestinal gluconeogenesis is a gut function that has been suggested to contribute to the metabolic benefits of RYGB in obese patients.MethodsWe studied the effects of DJB on body weight and glucose control in obese mice fed a high fat-high sucrose diet. Wild type mice and mice with a genetic suppression of intestinal gluconeogenesis were studied in parallel using glucose- and insulin-tolerance tests. Fecal losses, including excretion of lipids, were studied from the feces recovered in metabolic cages.ResultsDJB induced a dramatic decrease in body weight and improvement in glucose control (glucose- and insulin-tolerance) in obese wild type mice fed a high calorie diet, for 25 days after the surgery. The DJB-induced decrease in food intake was transient and resumed to normal in 7–8 days, suggesting that decreased food intake could not account for the benefits. Total fecal losses were about 5 times and lipid losses 7 times higher in DJB-mice than in control (sham-operated and pair-fed) mice, and could account for the weight loss of mice. The results were comparable in mice with suppression of intestinal gluconeogenesis. There was no effect of DJB on food intake, body weight or fecal loss in lean mice fed a normal chow diet.ConclusionsDJB in obese mice fed a high calorie diet promotes dramatic fecal loss, which could account for the dramatic weight loss and metabolic benefits observed. This could dominate the effects of the mouse genotype/phenotype. Thus, fecal energy loss should be considered as an essential process contributing to the metabolic benefits of DJB in obese mice.

Recent Trends of Microbiota-Based Microbial Metabolites Metabolism in Liver Disease

“…Various studies have confirmed that SCFAs participate in the regulation of NAFLD by activating G-protein-coupled receptor (GPR) 41 or 43, which are expressed in various areas, such as adipose, liver, tissues, peripheral blood, and intestinal cells ( 47 , 48 ). As per previous publications, intestinal gluconeogenesis (IGN) functions as a regulator of NAFLD via upregulation of hepatic insulin sensitivity and downregulation of hepatic glucose production (HGP) through the gut-brain-liver neural circuit ( 49 , 50 ).…”

Dietary Polyphenols to Combat Nonalcoholic Fatty Liver Disease via the Gut–Brain–Liver Axis: A Review of Possible Mechanisms

“…SCFAs act as important sources of nutrients and energy from the intestinal epithelium, which is critical for the maintenance of the intestinal homeostasis. SCFAs were demonstrated by a variety of studies to participate in the regulation of NAFLD by activating G-protein-coupled receptor (GPR)­41 or/and 43, which is expressed in the adipose, intestinal, liver, peripheral blood, or nervous tissues. , As reported, intestinal gluconeogenesis (IGN) functions as a regulator of the setup of NAFLD evidenced by an increase in hepatic insulin sensitivity and a decrease in HGP through a gut–brain–liver neural circuit, and it can be triggered by some beneficial macronutrients. , Interestingly, SCFAs, including propionate and butyrate, can induce IGN during the presence of de novo -synthesized glucose from the gut epithelium, which initiates the glucose signal to the brain via a GPR41-mediated neural circuit mechanism, thereby increasing insulin sensitivity and glucose tolerance. − In addition to activation of the GPR, SCFAs can directly enter the liver through the portal vein where they improve hepatic glycolipids homeostasis via the activation of AMPK in a peroxisome proliferators-activated receptors (PPAR)­γ-dependent manner . Emerging research has also implicated that SCFAs can travel across the blood–brain barrier (BBB) into CNS and affect the cellular biological mechanism of the neural development (microglia, BBB permeability, neurogenesis), thereby resulting in various physiological processes of the liver, including gluconeogenesis, insulin sensitivity, and AMPK activity. , The above evidence indicates that SCFAs acts as an important signaling molecule used for communication between the microbiota and the host tissues via the gut–brain–liver axis.…”

“…89,90 As reported, intestinal gluconeogenesis (IGN) functions as a regulator of the setup of NAFLD evidenced by an increase in hepatic insulin sensitivity and a decrease in HGP through a gut−brain−liver neural circuit, and it can be triggered by some beneficial macronutrients. 91,92 Interestingly, SCFAs, including propionate and butyrate, can induce IGN during the presence of de novo-synthesized glucose from the gut epithelium, which initiates the glucose signal to the brain via a GPR41-mediated neural circuit mechanism, thereby increasing insulin sensitivity and glucose tolerance. 93−95 In addition to activation of the GPR, SCFAs can directly enter the liver through the portal vein where they improve hepatic glycolipids homeostasis via the activation of AMPK in a peroxisome proliferators-activated receptors (PPAR)γ-dependent manner.…”

Metabolic Surgery and Cancer Risk: An Opportunity for Mechanistic Research

“…Many of these mechanisms are also linked to T2DM and CV risk (Table 3). These include increased insulin sensitivity [36,39], decreased insulinlike growth factor (IGF)-1 [37], altered intestinal bile acid concentration [45], decreased adipose tissue and systemic inflammation (with lower levels of circulating inflammatory cytokines) [36,52], a favorably altered gut microbiome [43,46] and epigenetic changes [42], decreased adipocyte size [41] (which allows more normal adipocyte functioning), decreased aromatase production [44] and enzymatic conversion of androgens to estrogen [36] thereby limiting the increase in circulating estrogen, lowering oxidative stress [38], and increasing intestinal gluconeogenesis [10,40]. Some of these proposed mechanisms are supported by MBS animal studies, as we outline in in Section 3.…”