Gut microbiota, nutrient sensing and energy balance.

The gastrointestinal (GI) tract is a highly specialized sensory organ that provides crucial negative feedback during a meal, partly via a gut-brain axis. More specifically, enteroendocrine cells located throughout the GI tract are able to sense and respond to specific nutrients, releasing gut peptides that act in a paracrine, autocrine or endocrine fashion to regulate energy balance, thus controlling both food intake and possibly energy expenditure. Furthermore, the gut microbiota has been shown to provide a substantial metabolic and physiological contribution to the host, and metabolic disease such as obesity has been associated with aberrant gut microbiota and microbiome. Interestingly, recent evidence suggests that the gut microbiota can impact the gut-brain axis controlling energy balance, at both the level of intestinal nutrient-sensing mechanisms, as well as potentially at the sites of integration in the central nervous system. A better understanding of the intricate relationship between the gut microbiota and host energy-regulating pathways is crucial for uncovering the mechanisms responsible for the development of metabolic diseases and for possible therapeutic strategies.

Impact of high-fat feeding on basic helix-loop-helix transcription factors controlling enteroendocrine cell differentiation.

BACKGROUND AND OBJECTIVES: Gut hormones secreted by enteroendocrine cells (EECs) play a major role in energy regulation. Differentiation of EEC is controlled by the expression of basic helix-loop-helix (bHLH) transcription factors. High-fat (HF) feeding alters gut hormone levels; however, the impact of HF feeding on bHLH transcription factors in mediating EEC differentiation and subsequent gut hormone secretion and expression is not known. METHODS: Outbred Sprague-Dawley rats were maintained on chow or HF diet for 12 weeks. Gene and protein expression of intestinal bHLH transcription factors, combined with immunofluorescence studies, were analyzed for both groups in the small intestine and colon. Gut permeability, intestinal lipid and carbohydrate transporters as well as circulating levels and intestinal protein expression of gut peptides were determined. RESULTS: We showed that HF feeding resulted in hyperphagia and increased adiposity. HF-fed animals exhibited decreased expression of bHLH transcription factors controlling EEC differentiation (MATH1, NGN3, NEUROD1) and increased expression of bHLH factors modulating enterocyte expression. Furthermore, HF-fed animals had decreased number of total EECs and L-cells. This was accompanied by increased gut permeability and expression of lipid and carbohydrate transporters, and a decrease in circulating and intestinal gut hormone levels. CONCLUSIONS: Taken together, our results demonstrate that HF feeding caused decreased secretory lineage (that is, EECs) differentiation through downregulation of bHLH transcription factors, resulting in reduced EEC number and gut hormone levels. Thus, impaired EEC differentiation pathways by HF feeding may promote hyperphagia and subsequent obesity.

Decreased intestinal nutrient response in diet-induced obese rats: role of gut peptides and nutrient receptors.

BACKGROUND AND AIMS: Diet-induced obesity (DIO) is an excellent model for examining human obesity comprising both genotypic and environmental (diet) factors. Decreased responsiveness to peripheral satiety signaling may be responsible for the hyperphagia in this model. In this study, we investigated responses to nutrient-induced satiation in outbred DIO and DIO-resistant (DR) rats fed a high-energy/high-fat (HE/HF) diet as well as intestinal satiety peptide content, intestinal nutrient-responsive receptor abundance and vagal anorectic receptor expression. METHODS: Outbred DIO and DR rats fed a HE/HF diet were tested for short-term feeding responses following nutrient (glucose and intralipid (IL)) gastric loads. Gene and protein expressions of intestinal satiety peptides and fatty acid-responsive receptors were examined from isolated proximal intestinal epithelial cells and cholecystokinin-1 receptor (CCK-1R) and leptin receptor (LepR) mRNA from the nodose ganglia of DIO and DR animals. RESULTS: DIO rats were less responsive to IL- (P<0.05) but not glucose-induced suppression of food intake compared with DR rats. DIO rats exhibited decreased CCK, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1; P<0.05 for each) protein expression compared with DR rats. Also, DIO rats expressed more G-protein-coupled receptor 40 (GPR40; P<0.0001), GPR41 (P<0.001) and GPR120 (P<0.01) relative to DR rats. Finally, there were no differences in mRNA expression for CCK-1R and LepR in the nodose ganglia of DIO and DR rats. CONCLUSIONS: Development of DIO may be partly due to decreased fat-induced satiation through low levels of endogenous satiety peptides, and changes in intestinal nutrient receptors.

Current and emerging concepts on the role of peripheral signals in the control of food intake and development of obesity.

The gastrointestinal peptides are classically known as short-term signals, primarily inducing satiation and/or satiety. However, accumulating evidence has broadened this view, and their role in long-term energy homeostasis and the development of obesity has been increasingly recognised. In the present review, the recent research involving the role of satiation signals, especially ghrelin, cholecystokinin, glucagon-like peptide 1 and peptide YY, in the development and treatment of obesity will be discussed. Their activity, interactions and release profile vary constantly with changes in dietary and energy influences, intestinal luminal environment, body weight and metabolic status. Manipulation of gut peptides and nutrient sensors in the oral and postoral compartments through diet and/or changes in gut microflora or using multi-hormone 'cocktail' therapy are among promising approaches aimed at reducing excess food consumption and body-weight gain.

Up-regulation of intestinal type 1 taste receptor 3 and sodium glucose luminal transporter-1 expression and increased sucrose intake in mice lacking gut microbiota.

The chemosensory components shared by both lingual and intestinal epithelium play a critical role in food consumption and the regulation of intestinal functions. In addition to nutrient signals, other luminal contents, including micro-organisms, are important in signalling across the gastrointestinal mucosa and initiating changes in digestive functions. A potential role of gut microbiota in influencing food intake, energy homeostasis and weight gain has been suggested. However, whether gut microbiota modulates the expression of nutrient-responsive receptors and transporters, leading to altered food consumption, is unknown. Thus, we examined the preference for nutritive (sucrose) and non-nutritive (saccharin) sweet solutions in germ-free (GF, C57BL/6J) mice compared with conventional (CV, C57BL/6J) control mice using a two-bottle preference test. Then, we quantified mRNA and protein expression of the sweet signalling protein type 1 taste receptor 3 (T1R3) and α-gustducin and Na glucose luminal transporter-1 (SGLT-1) of the intestinal epithelium of both CV and GF mice. Additionally, we measured gene expression of T1R2, T1R3 and α-gustducin in the lingual epithelium. We found that, while the preference for sucrose was similar between the groups, GF mice consumed more of the high concentration (8 %) of sucrose solution than CV mice. There was no difference in either the intake of or the preference for saccharin. GF mice expressed significantly more T1R3 and SGLT-1 mRNA and protein in the intestinal epithelium compared with CV mice; however, lingual taste receptor mRNA expression was similar between the groups. We conclude that the absence of intestinal microbiota alters the expression of sweet taste receptors and GLUT in the proximal small intestine, which is associated with increased consumption of nutritive sweet solutions.

Differential feeding behavior and neuronal responses to CCK in obesity-prone and -resistant rats.

Deficits in satiation signals are strongly suspected of accompanying obesity and contributing to its pathogenesis in both humans and rats. One such satiation signal is cholecystokinin (CCK), whose effects on food intake are diminished in animals adapted to a high fat diet. In this study, we tested the hypothesis that diet-induced obese prone (OP) rats exhibit altered feeding and vagal responses to systemic (IP) administration of CCK-8 compared to diet-induced obese resistant (OR) rats. We found that CCK (4.0 microg/kg) suppressed food intake significantly more in OP than OR rats. To determine whether enhanced suppression of feeding is accompanied by altered vagal sensory responsiveness, we examined dorsal hindbrain expression of Fos-like immunoreactivity (Fos-Li) following IP CCK injection in OP and OR rats. After 4.0 microg/kg CCK, there were significantly more Fos-positive nuclei in the NTS of OP compared to OR rats. Treatment with 8.0 microg/kg CCK resulted in no significant difference in food intake or in Fos-Li between OP and OR rats. Also, we found that OP rats were hyperphagic on a regular chow diet and gained more weight compared to OR rats. Finally OP rats had decreased relative fat pad mass compared to OR rats. Collectively, these results show that OP rats exhibit a different behavioral and vagal neuronal responses to CCK than OR rats.