Gut, Nutrient Sensing and Energy Balance in Obesity Yunsook Lim, Ph.D Department of Food and Nutrition Kyung Hee University Global Obesity Obesity Prevalence in Korea Obesity Genetic factors Environmental & Social factors Interact on Central & peripheral Physiological factors Psychological factors OBESITY Excessive fat accumulation Low-grade chronic inflammation Energy Balance • A balance between energy intake and energy expenditure • Food intake: a key factor to control energy intake • A balance between the sensation of hunger preceding a meal and the sensation of fullness after nutrient absorption. Gut • Digestive organs • The first site of interaction between ingested nutrients and the host • Control of food intake and regulation energy balance Nutrient Sensing in the Gut • The largest endocrine organ in the body • Produce over 20 hormones in spite of enteroendocrine cells (EECs) being a small representation(1%) of the total epithelial cell population • To the controls of food intake, termination of a meal(satiation) and length of intermeal interval(satiety) • Co-expression of the gut peptides between the various EECs Gut-Brain Axis in Food Intake Gut-Brain Axis in Food Intake Brain Gut Simplified representation of potential action of gut peptides on the hypothalamus Energy Homeostasis via Gut-Brain Axis in Obesity • A dysregulated balance between the sensation of hunger preceding in a meal and the sensation of fullness after nutrient absorption • Modulation of gastric distention, changes in gut motility and the secretion of gastrointestinal hormones such as ghrelin, cholecystokinin (CCK), peptide YY3-36, glucagonlike peptide (GLP), and oxytomodulin Nutrient Sensing in the Gut • Nutrients activate sensing mechanisms in the duodenum to trigger a gut brain driven negative feedback system to inhibit exogenous nutrient intake and endogenous nutrient production by the liver. • Metabolic homeostasis is maintained in the response to nutrient intake. • Intestinal nutrient sensing mechanisms fail to lower food intake and glucose production, leading to a disruption of metabolic homeostasis in obesity. Gluconeogenesis in the Gut • Gluconeogensis is a new intestinal metabolic function. • Gut participates in the regulation of glucose homeostasis via its capacity to uptake and metabolize glucose. • Glucose 6-phosphatase gene for gluconeogenesis is expressed in the small intestine during fasting or insulin deficit condition such as diabetes. • In particular, glucose in the portal vein initiates activation of vagal nerve and activation of nerve in the nucleus of the solitary tract and in the hypothalamus. • Glucose produced by gluconeogenesis in the gut leads to regulation of food intake and energy homeostasis via portal glucose sensing. Protein Sensing in the Gut • Protein enriched diets (PED) initiate satiety effects indirectly via intestinal gluconeogenesis and portal glucose sensing. • PED induced genes related to gluconeogenesis. • Peptides derived from the protein digestion in the portal vein might be involved in μ-opioid receptor (MOR) related control of food intake via intestinal gluconeogenesis. Lipid Sensing in the Gut • After absorption of lipids into duodenal enterocytes, long chain fatty acids (LCFA) from lipids are metabolized into LCFA-CoA by acyl-CoA synthase. • Continuous intraduodenal intralipids infusion elevates duodenal LCFA-CoA levels and lowers glucose production. • Intraduodenal lipid accumulation lowers food intake through release of CCK. Lipid Sensing in the Gut • However, high fat diet feeding causes PKC-δ and CCK resistance in lowering glucose production. • High fat diet induces obesogenic microbiota and subsequently alters CCK action. Carbohydrates and Sugars in the Gut • Intestinal infusion of carbohydrates and sugars have been reported to suppress food intake which might be related to secretion of gut peptides. • The longer the length of the carbohydrates infused, the greater the reduction of food intakes (maltotriose vs maltose). The Gut Microbiota • The entire microbial community colonizing within the GI tract • Interactive roles in influencing intestinal nutrient absorption and sensing • Aberrations in the gut microbiota: a potential contributing factor in obesity Gut Microbiota Role of Gut Microbiota Gut Microbiota in Obesity Tremaroli and Backhed (2012) Nature 489; pp242-249 Obese Microbiota Role of Gut Microbiota in Obesity • Germ free (GF) mice have less adiposity than normal mice, and are resistant to high fat (HF) diet induced obesity. • Increased AMP acivated protein kinase (AMPK) in colonical epithelial cells and hepatocytes in GF mice. • GF mice colonized w/ microbiota derived from an obese HF-fed donor results in an increase in body. Role of Gut Microbiota in Obesity • The gut microbiota derived lipopolysaccharides (LPS) is associated with low grade of inflammation in obesity and metabolic diseases. • After only 2 weeks of HF feeding, circulation LPS levels were 2-3 fold increased in type 2 diabetes. NASH/NAFLD Tremaroli and Backhed (2012) Nature 489; pp242-249 Dietary Fibers and Gluconeogeneis in the Gut • Soluble dietary fiber is fermented by bacteria in the distal gut to produce short chain fatty acids (SFA) including acetate, propionate and butyrate. • Fiber enriched diets are known to improve insulin sensitivity and glucose tolerance in lean and obese subjects. • The benefits of dietary fibers might come from SFA through regulation of energy homeostasis. • In particular, propionate is a possible substrate of gluconeogenesis and increases intestinal gluconeogenesis and portal glucose sensing. • Moreover, propionate stimulates gluconeogenesis related gene expression via a portal hypothalamic neural circuit by activation of the free fatty acid receptor(FFAR) whereas butyrate stimulate the expression of gluconeogenesis related genes directly in the enterocytes. Summary • The gut has multi-functions including controls of food intake, gluconeogensis, hormone secretion and nutrient sensing for energy homeostasis. • Obese condition alters nutrient sensing mechanisms and induces obese microbiota in the gut. • Rearrangement of an aberrant nutrient sensing mechanism and obese microbiota would be a potential therapeutic approach in obesity. Thank you for your attention
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