Week 1- PAT-3.02 Obesity 2 .pdf

Pathogenesis of Obesity, Part 1 In-person Class 1 BMS 200 Week 1 References: REFERENCE: Oussaada SM, van Galen KA, Cooiman, MI, Kleinendorst L, Hazebroek EJ, van Haelst MM, Ter Horst KW, Serlie MJ. The pathogenesis of obesity. 2019;92:26-27. https://doi-org.ccnm.idm.o...

Pathogenesis of Obesity, Part 1 In-person Class 1 BMS 200 Week 1 References: REFERENCE: Oussaada SM, van Galen KA, Cooiman, MI, Kleinendorst L, Hazebroek EJ, van Haelst MM, Ter Horst KW, Serlie MJ. The pathogenesis of obesity. 2019;92:26-27. https://doi-org.ccnm.idm.oclc.org/10.1016/ j.metabol.2018.12.012 von Loeffelholz C, Birkenfeld AL. Non-Exercise Activity Thermogenesis in Human Energy Homeostasis. Endotext [Internet]. MA. 2022 https:// www.ncbi.nlm.nih.gov/books/NBK279077/ O’Rahilly S, Farooqi I. Pathobiology of Obesity. In: Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J. eds. Harrison's Principles of Internal Medicine, 21e. McGraw Hill; 2022. Accessed July 13, 2023. https://accessmedicine-mhmedical-com.ccnm.idm.oclc.org/content.aspx? bookid=3095&sectionid=265445670 Review from 150: Insulin Resistance & Obesity Most important environmental risk factor for insulin resistance is obesity ▪ Central obesity seems to be more crucial ▪ A separate risk factor from obesity is lack of exercise Most cases of insulin resistance are caused by a combination of genetic and environmental risk factors… ▪ … but don’t forget that T2DM is highly heritable ▪ Thought that about 5% of population-wide variance in body weight is due to genetic causes, but environment-gene interactions make this very difficult to study Review from 150: Obesity FAQs Do obese people eat more? ▪ Often, but not always In studies that do not record exact caloric intake, often there is a poor association between body weight and questionnaire- reported caloric intake In studies that record caloric intake more closely, the association is better Obese people and those with glucose intolerance often have impaired satiety mechanisms – i.e. poorly-characterized leptin resistance Do obese people “burn less energy”? ▪ This is a complicated question: In states where weight loss is not occurring, the obese person seems to use more calories than someone who is lean but may use less calories than someone who is lean during weight loss states Many obese people do have reduced BMR, though most don’t Literature still developing around this area Review from 150: Regulation of body weight and appetite Satiety signals: Leptin, GLP1, CCK, PYY, vagal afferents “Hunger” signals: Ghrelin (released by the stomach during fasting) All of these act on different nuclei in the hypothalamus Review from 150: Controllers of appetite Review from 150: Insulin Resistance and visceral fat Non-esterified fatty acids (NEFA) increase insulin resistance ▪ More released from central fat than peripheral fat ▪ Increased intracellular concentrations of NEFA cause serine phosphorylation of insulin receptor – which inactivates it (tyrosine phosphorylation activates it) Adipokines modify sensitivity of insulin receptor ▪ Adipose tissue is endocrine tissue – protein hormones from fat cells (adipokines) increase sensitivity of insulin receptor and increase activity of enzymes that oxidize NEFA Increased NEFA oxidation mediated by AMP-K, a protein kinase activated by metformin Anti-hyperglycemic adipokines: leptin, adiponectin (drops in T2DM) Hyperglycemic adipokines: resistin, retinol-binding-protein 4 Pro-inflammatory cytokines also secreted by fat cells, and decrease insulin receptor sensitivity Visceral obesity, insulin resistance, and inflammation This was briefly discussed in BMS 150 (next slide) Visceral adipocytes: ▪ Recruit macrophages and activate them ! production of pro-inflammatory cytokines (TNF-alpha, IL-6) Expression of MCP-1 (a chemokine) brings monocytes into visceral fat as well as production of pro-inflammatory cytokines by the adipocyte Elevated systemic levels of IL-6 ! increased production of CRP by the liver ▪ Insulin resistance in visceral adipocytes ! increased concentrations of free fatty acids ! activation of DAMPs in many cells increased production of pro-inflammatory cytokines ▪ Pro-inflammatory cytokines cross-talk with intracellular signaling cascades that lead to insulin resistance (serine phosphorylation of the insulin receptor) Kahn et. Al., J Clin Invest. 2019 Oct 1; 129(10): 3990–4000; doi: 10.1172/JCI129187  Review from 150: Chronic Inflammation and obesity Systemic inflammatory effects of obesity ▪ excessive lipid build-up can stress the adipocyte (ROS) ▪ free fatty acids in high concentrations may bind to PAMP-R within the adipocyte both of the above can lead As shown above, pro- to the production of IL-6 inflammatory cytokines lead and TNF-alpha by the adipocyte to insulin resistance, and can contribute to type II diabetes Review from 150: Insulin Resistance and visceral fat 10 Obesity - Definitions What is overweight? What is obesity? ▪ BMI definition (most used): Overweight ! BMI ≥ 25 kg/ m2 Obesity ! BMI ≥ 30 kg/m2 ▪ Waist:hip ratio for obesity (sometimes used): Men ! ratio > 0.90 Women ! ratio > 0.85 Advantages to using each definition? Disadvantages? Obesity - Definitions EE = Energy expenditure The total amount of energy we expend, measured in kcal/day Consists of: ▪ Resting metabolic rate (RMR) – metabolism of an individual at rest Energy requirements of respiration, circulation, etc. ▪ Activity-related energy expenditure (AEE) – exactly what it sounds like Exercise activity thermogenesis (EAT) – energy used during “dedicated exercise” Non-exercise activity thermogenesis (NEAT) – energy used when an individual is moving, but “not exercising” ! much larger component of AEE ▪ Diet-induced thermogenesis (DIT) – increase in metabolic rate associated with ingestion of food and post-absorptive heat production Ousaada et. al., Metab Clin Exp. 92: 26 – 36, 2019 Energy expenditure breakdown Model of human energy expenditure components ▪ Exercise-related physical activity is comparable to exercise-related activity thermogenesis (EAT), while spontaneous physical activity is comparable to non-exercise activity thermogenesis (NEAT) ▪ In most people, EAT is much, much less than NEAT In those who train regularly, it can be 15 – 30% of EE (very regular, dedicated exercise) 2 hours of training/week – 1-2 % of inter- individual variance ▪ Note that parts of spontaneous physical activity are beyond voluntary control, also called “fidgeting.” fidgeting can consume between 100 – 800 kcal/ day Ousaada et. al., Metab Clin Exp. 92: 26 – 36, 2019 https://www.ncbi.nlm.nih.gov/books/NBK279077/ RMR RMR = energy expenditure in an individual that is at rest and has not recently eaten Proportion of EE due to RMR varies between individuals ▪ If sedentary, 60 – 75% of total daily EE Main determinant of RMR is fat-free mass (FFM) ▪ Main component of FFM is weight of skeletal muscle ▪ also includes bone, visceral organs, extra-cellular fluid RMR varies from 2 – 10% in the same individual ▪ time of day, temperature season, etc. as well as errors in measurement RMR varies much more between individuals, between 7.5 and 18% ▪ Amount of FFM is the main determinant of inter-individual variability – about 62% ▪ Over 25% of inter-individual variation in RMR is not well understood – assumed to be genetic/molecular differences Ousaada et. al., Metab Clin Exp. 92: 26 – 36, 2019 Components of daily EE a) total EE expenditure b) EE per kg of FFM Ousaada et. al., Metab Clin Exp. 92: 26 – 36, 2019 RMR vs. BMR RMR has less stringent requirements than BMR Basal metabolic rate (BMR): ▪ Completely rested subjects in the morning, after 8 hours of sleep, fasting for 12 hours, and at a room temperature of between 22 – 26 Celsius ▪ 80% of variations in BMR are due to FFM variations (same as RMR) RMR: ▪ post-absorptive (i.e. not right after a meal) state at any time of day, at rest ▪ can vary from BMR by 10% https://www.ncbi.nlm.nih.gov/books/NBK279077/ NEAT - generalities NEAT = “portion of daily energy expenditure resulting from spontaneous physical activity that is not specifically the result of voluntary exercise” ▪ variation can be up to 2000 kcal/day in two similar- sized individuals ▪ differences in occupations, leisure activities, molecular/genetic factors, seasonal effects ▪ The most variable aspect of energy expenditure on a population basis 6-10% of EE in individuals with a sedentary lifestyle up to 50% in highly active individuals (often those that are standing or constantly moving around in their occupation) https://www.ncbi.nlm.nih.gov/books/NBK279077/ NEAT – impact of diet and exercise Measurement of NEAT is extremely complex, and studies vary in terms of the impact of dietary changes With overfeeding: ▪ a significant minority of people will increase NEAT, to the point where increased activity compensates for increased calories consumed ▪ the majority do not increase NEAT to compensate for over- feeding, but total EE does still increase somewhat With underfeeding: ▪ RMR and NEAT both decrease in those that are inactive 20% weight loss ! 320 – 500 kcal/day reduction in EE Due mostly to losses in FFM ▪ Studies suggest that those that undergo exercise regimens with underfeeding will not suffer as large a decrease in NEAT https://www.ncbi.nlm.nih.gov/books/NBK279077/ Models of energy expenditure Independent model of energy expenditure: ▪ changes in EE are independent of the energy you “budget” for a behaviour (NEAT, EAT) ▪ Therefore, if you increase your NEAT & EAT, your total EE goes up… and it’s “easier” to lose weight Compensation/allocation model of energy expenditure ▪ if you increase the energy expenditure in one area (EAT for example), you decrease the expenditure in another (RMR or NEAT) There is evidence for both models Literature on weight loss also identifies two types of populations: ▪ Compensator – if a compensator is overfed, then spontaneous physical activity (NEAT) increases ▪ Non-compensator – with overfeeding, less increase in EE, mostly due to less of an increase in NEAT 57% of variability of spontaneous physical activity is believed to be a result of inheritance/ genetics https://www.ncbi.nlm.nih.gov/books/NBK279077/  Exercise, diet, and insulin resistance With weight loss due to caloric restriction, skeletal muscles seem to become more efficient ▪ not sure why – in rats, the following was found: decreases SNS activity ! decreased cardiovascular energy expenditure and skeletal muscle energy expenditure a molecular “switch” to isoforms of the myosin heavy chain that expend less ATP Reductions in the activity of the SNS as well as reductions in the release of thyroid hormone with underfeeding also contribute to decreases in EE (RMR) Exercise causes translocation of GLUT-4 transporters to the sarcolemma ! improved glucose transport from blood to “busy” muscle… impact on insulin resistance? https:// www.ncbi.nlm.nih.gov/ books/NBK279077/ Small Group Activity Dive into the following paper: ▪ https://www-sciencedirect-com.ccnm.idm.oclc.org/ science/article/pii/S0026049519300071?via%3Dihub ▪ It’s in your folder for today Each group look specifically for the following information: Group 1 – definition of diet-induced thermogenesis Group 2 – do some macronutrients have different degrees of diet-induced thermogenesis? Which ones have the highest? Group 3 – does the temperature of food impact diet- induced thermogenesis? How do we regulate energy intake? Homeostatic pathway – basically, stimulates eating behaviour when energy stores are low, and suppresses it in ▪ “Major peripheral players” – sense when nutrients are present or absent: Adipose tissue, stomach, intestines, special senses, pancreas, liver These areas release the many, many endocrine signals that modulate appetite and energy expenditure ▪ “Major central players” – nerves and central nervous system nuclei/connections that integrate this information and translate it to a “sense of hunger” Vagus nerve, brainstem, hypothalamic nuclei, cortex, aspects of the limbic system Ousaada et. al., Metab. Clin. Exp. 92, 26-36, 2019; doi.org/10.1016/j.metabol.2018.12.012  Simple “CNS portion” of the homeostatic model The arcuate nucleus of the hypothalamus (ACN) and the paraventricular nucleus (PVN) seem important in integrating signals from the periphery and the CNS Note: AGRP neurons also secrete NP Y When nutrients are present, POMC NP Y stimulates food intake (separate neurons in the ACN mechanism) release MSH ! PVN drives behaviour to When nutrients are present, AGRP neurons are inhibited ! less AGRP reduce eating and ▪ AGRP blocks the MSH receptors (MC4R) increase energy expenditure Therefore, satiety is mediated by increased MSH signaling, either directly (MSH release) or indirectly (inhibition of AGRP release) Serotonin signaling and the homeostatic pathway Serotonergic neurons in the midbrain (the raphe nucleus) project to the arcuate nucleus as well as nuclei involved in the hedonic pathway ▪ Increased serotonin signaling ! activation of MSH neurons, inhibition of AGRP/NPY neurons… Impact on satiety? ▪ Lorcarserin is a 5-HTc receptor agonist which can induce weight loss in obese subjects ▪ Signaling mechanisms are complicated and can involve changes in serotonin release, modulation of serotonin receptors, and upregulation/downregulation of serotonin transporters Quite a bit of human data that suggests that it is important in satiety and weight regulation Ousaada et. al., Metab. Clin. Exp. 92, 26-36, 2019; doi.org/10.1016/j.metabol.2018.12.012 How do we regulate energy intake? Hedonic model – food intake is driven by reward pathways in the brain, less by nutrient availability ▪ Therefore, “less reliance” on feedback from peripheral sites that are exposed to nutrients However, this is likely an oversimplification, as nutrients and hormones associated with nutrient intake have recently been found to directly influence these brain areas ▪ “Major central players” – many of these brain areas are important areas of the CNS that mediate reward Lateral hypothalamus, ventral tegmental area, nucleus accumbens (part of ventral striatum), limbic system nuclei Major neurotransmitters implicated are dopamine as well as the endogenous opioids (enkephalins, endorphins, etc.) ▪ Reward = pleasant sensations associated with eating, and that can often drive eating in the absence of hunger Ousaada et. al., Metab. Clin. Exp. 92, 26-36, 2019; doi.org/10.1016/j.metabol.2018.12.012  Simple “CNS portion” of the hedonic model Basic pathway: The lateral hypothalamus projects to a midbrain area, the ventral tegmental area Dopaminergic neurons in the ventral tegmental area project diffusely to the: ▪ Nucleus accumbens ▪ Amygdala ▪ Prefrontal and orbitofrontal cortex The VTA and NA also “talk back” to the hypothalamus Stogios et. Al., Nutrients 2020, 12, 3883; doi:10.3390/nu12123883, Fig 1 Lutter & Nestler, J Nutr. 2009, 139:629-632; doi: 10.3945/jn.108.097618, Fig. 1 How do we regulate energy intake? Are the hedonic and homeostatic pathways separate? ▪ Not at all… the hedonic pathway can impact the arcuate nucleus ▪ As well, activity (or lack of it) in the homeostatic pathway will modulate the reward pathway ▪ It seems like there is a disruption in the “balance” between these two pathways in obese persons ▪ In the end, it appears that the “master integrator” is the hypothalamus ! it weighs information from both pathways to drive eating behaviour Ousaada et. al., Metab. Clin. Exp. 92, 26-36, 2019; doi.org/10.1016/j.metabol.2018.12.012 Energy intake and reward deficiency Reward deficiency hypothesis ▪ In all of us, delicious (often fatty, often sweet) food rewards us… the reward is that adjective “delicious”, and all the positive feelings that accompany eating something you like Viewing it simply ! hedonic pathway activation ▪ Human evidence seems to indicate that lean subjects have better activation of the reward pathway than obese subjects… therefore it’s possible obese subjects are “reward deprived”… Striatal dopamine release seems to be impaired in those who are obese, with decreased D2/D3 receptor activation ▪ In addition, those who are obese may anticipate reward more when expecting a meal In those who are obese, visual palatable food stimuli elicit greater activation of the corticolimbic system Increased reward expectation + decreased reward upon eating ! increased eating behaviour Ousaada et. al., Metab. Clin. Exp. 92, 26-36, 2019; doi.org/10.1016/j.metabol.2018.12.012  The “peripheral” homeostatic players Adipose-derived: Leptin, adiponectin, resistin, retinol- binding protein 4 (RBP-4), FGF-21 GI-derived: Stomach – ghrelin (orexigenic) Rest of the GI tract: GLP-1, CCK, peptide YY, oxyntomodulin Pancreas: Insulin Interaction of peripheral and central players in the homeostatic system Importance of the hypothalamus Surrounds the 3rd ventricle and the CSF has some “crossover” with molecules from the peripheral circulation Parts of the hypothalamus have a “leakier” BBB However, many peripheral signals can impact other brain areas (transported across BBB, i.e. insulin) As well, the vagus synapses with the hypothalamus, and is important in relaying peripheral messages Segue - Types of fat White fat – predominant form of adipose tissue, serves as a store of triglycerides, and visceral adipose tissue (within the peritoneum, especially omental fat) is an important endocrine organ ▪ Storage vacuole – specialized phospholipid monolayer with local adaptations to limit lipid peroxidation in the presence of free radicals Brown fat – steadily decreases as we age, most found in infants in particular areas of the body, main role is thermogenesis… and energy balance? ▪ Uncoupling protein in mitochondria “burns fat” (beta oxidation) without generating ATP ▪ Allows leakage of protons across inner mitochondrial membrane ! heat production ▪ Regulated by catecholamines (activated by beta-3 receptors) ▪ Small fat vacuoles, many more mitochondria White fat can “brown” with exercise, cold, sympathetic stimulation ▪ Known as beige, or brite (brown-like) adipose tissue, looks like brown- fat cells interspersed with white fat cells Kahn et. Al., J Clin Invest. 2019 Oct 1; 129(10): 3990–4000; doi: 10.1172/JCI129187 Location/characteristics of different types of adipose tissue Kahn et. Al., J Clin Invest. 2019 Oct 1; 129(10): 3990–4000; doi: 10.1172/JCI129187 Homeostatic pathway mediators Leptin: Secreted by white adipocytes in the presence of insulin, inhibited by catecholamines (so increased post-prandially) Anorexigenic – suppresses NPY and AGRP, increases MSH secretion from the arcuate nucleus of the hypothalamus ▪ Those with congenital leptin deficiencies (very rare) become obese due to hyperphagia Discovered in 1994 and generated lots of excitement ▪ The weight loss pill/molecule/injection! ▪ Alas, it was not to be… Obese subjects tend to have elevated leptin levels and the hypothalamus is resistant to leptin ▪ May be mediated by gliosis/inflammation in the hypothalamus, but yet to be conclusively proven Kahn et. Al., J Clin Invest. 2019 Oct 1; 129(10): 3990–4000; doi: 10.1172/JCI129187 Homeostatic pathway mediators Insulin: Secreted by pancreatic beta-cells in response to elevated blood glucose and some amino acids Receptors for insulin are present in the ventral striatum, and are linked to increased dopamine signaling in that area ▪ Increased hedonic pathway signaling can amplify homeostatic satiety signaling in the hypothalamus Kahn et. Al., J Clin Invest. 2019 Oct 1; 129(10): 3990–4000; doi: 10.1172/JCI129187 GI hormones and homeostatic appetite signaling Ghrelin – released by cells in the gastric fundus in response to fasting ▪ Stimulates hunger pathways (i.e. amplification of AGRP and NP Y, inhibition of MSH) likely by stimulating the vagus nerve There are receptors in the brain for ghrelin, though ▪ Only orexigenic hormone ▪ Obesity: Fasting levels of ghrelin are negatively correlated with BMI Obese patients might not suppress ghrelin as effectively after a meal GI hormones and homeostatic appetite signaling We’ve seen all of these before in BMS 150 – secreted by enteroendocrine cells in various parts of the GI tract (next slide) CCK is released proximally in the small intestine (duodenum) ▪ Slows gastric emptying, and increases sensations of satiety GLP-1 and PYY are released more distally in the intestine ▪ also slow gastric emptying and increase satiety The brain expresses receptors for all of these enteroendocrine hormones ▪ However, in those with transection of the vagus, their satiety-inducing effect is blunted or abrogated Vagal afferents have receptors for all of these molecules ▪ Likely that much of the satiety effect is through vagus ! NTS of the brainstem ! hypothalamus Longo et. Al., Acta Diabetologica (2023) 60:1007–1017; doi: 10.1007/s00592-023-02088-x BMS 150 review Cell Location Hormone (Stimulus) Main Hormonal Functions Stomach, Somatostatin Generally “turns down” the release of D duodenum, (many different stimuli cause hormones from nearby cells pancreas release) ECL – stomach ECL – histamine (stimulated ECL – stimulates acid production EC – stomach, by vagus) EC – increased motility EC, ECL small and large EC – serotonin, substance P intestines (mechanical, neural, endo) Gastrin (amino acids in the Increases secretion of stomach acid G Stomach stomach, vagal stimulation, gastrin-releasing peptide) Small Intestine CCK (fats and proteins in the Pancreatic enzyme secretion, gallbladder I* (especially duodenum) contraction, satiety duodenum) Inhibits gastric acid secretion Glucagon-like peptide GLP-1 - Insulin secretion, satiety (amino acids & carbs) Inhibits gastric acid secretion L* Small intestine Peptide YY (distal small Peptide YY – inhibits gastric secretion & intestine) motility – slows gastric emptying Motilin (fasting) Migrating motor complex Mo Small intestine Secretin (acid in small Bicarbonate and water secretion from S Small intestine intestine, especially pancreas duodenum) Inhibits gastric acid secretion, emptying Cause and effect in regulation of appetite Most human data shows association between a component of the homeostatic/hedonic pathway and obesity ▪ correlation does not necessarily imply causation For example: ▪ high-calorie snacking in lean subjects can change serotonin transporter activity ! impaired serotonin signaling ▪ striatal dopamine signaling can be increased after bariatric surgery-induced weight loss ▪ In these situations, weight loss or gain ! changes in the pathways Ousaada et. al., Metab. Clin. Exp. 92, 26-36, 2019; doi.org/10.1016/j.metabol.2018.12.012 Adipokines, insulin resistance, and obesity Is adiponectin part of the homeostatic pathway? produced mostly by white adipose tissue (particularly subcutaneous white fat), but other tissues (muscle, bone, liver) can secrete it As visceral fat and insulin resistance increase, adiponectin tends to decrease Not enough evidence to say that it stimulates or inhibits appetite in humans However, adiponectin does: ▪ increase insulin sensitivity ▪ decrease fat accumulation in the liver and hepatic glucose output Other adipokines can increase insulin resistance – in particular resistin (perhaps more important in mice) and retinol-binding protein 4 (RBP-4) Kahn et. Al., J Clin Invest. 2019 Oct 1; 129(10): 3990–4000; doi: 10.1172/JCI129187 Summary of Obesity Complications System Description Dyslipidemia Increased TG and LDL, systemic inflammation ! atherosclerosis Fatty Liver Disease Ectopic fat in hepatocytes ! fibrosis ! cirrhosis Type 2 Diabetes & insulin Visceral fat has a large impact on overall insulin sensitivity resistance PCOS/ Hypogonadism reduced testosterone in hypogonadism, likely due to related to insulin resistance Hormonal abnormalities in PCOS ! increased androgen production (likely due to insulin resistance) which is partially converted to estrogens by visceral fat ! dysregulated cycles Skin Skin folds ! increased risk of fungal infection acanthosis nigricans Cardiovascular Increase atherothrombotic vascular disease independent of diabetes type 2, but still suspected to be related to insulin resistance Harrison’s Principles of Internal Medicine 2022 Summary of Obesity Complications System Description Respiratory Dyspnea due to increased mass and increased pressure on thoracic cage, increased adipose tissue around upper airways GI Increased intraabdominal pressure can result in reflux esophagitis, also increased risk of gallstones Rheumatic Increased OA of knees/hips, but NO increase in RA or other inflammatory joint disease Cancer As BMI increases by 5 kg/m2 ! cancer mortality increases by 10% Infections Increased susceptibility to bacterial wound infections and SARS-COV2 complications CNS Increased risk of dementia & stroke (atherosclerosis) Increased incidence of idiopathic intracranial hypertension Harrison’s Principles of Internal Medicine 2022 How can the gut microbiota influence our food intake? Introducing - Microbiota-Gut-Brain Axis (MGBA): Composed of ANS, ENS, Spinal nerves, HPA axis, Immune system, Enteroendocrine cells (EEC’s) and Microbiome CNS receives and directs input via spinal nerves that connect with ENS ENS receives and directs input via EEC’s which in terms can be modified by and can influence the composition of the microbiome HPA: it’s unclear the specific role that it plays but appears to be implicated in MGBA; chronic elevations of cortisol are correlated with changes in gut microbiota function Immune system facilitates a symbiotic relationship with commensal gut microbiota Vagus nerve; directly detects intestinal distention via mechanoreceptors AND vagal chemoreceptors connect to EEC’s; appear to be activated by changes in microbiota (animal studies) Von Son 2021, Longo 2023 How can the gut microbiota influence our food intake? Possible mechanisms: Changes in gut microbiota seen in obesity result in increased gut permeability that allow LPS to enter circulation and trigger proinflammatory state within adipocytes and systematically, which can then promote insulin insensitivity Obese humans have increase in plasma LPS post high-fat meal versus lean humans Enteroendocrine cells modify their secretions (serotonin, ghrelin, CCK, GLP-1, PYY) in response to microbial metabolites like SCFA’s, these can then influence insulin, gastric acid and bile acid secretion Vagus nerve connects gut to nucleus of solitary tract which connects to hypothalamic arcuate nucleus that is involved in energy balance Vagotomy has been associated with changes in body weight Von Son 2021, Longo 2023 How can the gut microbiota influence our food intake? Possible mechanisms: Gut microbiome produces SCFA’s, GABA, dopamine and serotonin SCFA’s have been implicated in regulating satiety: Increase PYY and GLP-1 secretion Stimulating vagus nerve Passing through BBB and inducing anorexigenic signals Reducing fat accumulation in adipocytes Inducing thermogenesis and increased energy expenditure Increase leptin production HOWEVER, intervention studies failed to show benefit of supplementary SCFA’s on weight in metabolic syndrome Von Son 2021, Longo 2023 How can the gut microbiota influence our food intake? Possible mechanisms: Homeostatic Pathway Observations: Bifidobacterium and Lactobacillus positively correlate with leptin (promotes satiety) and negatively with ghrelin (promotes hunger) Following H. pylori eradication increase in Bacteroidetes/ Firmicutes ratio correlates with reduced ghrelin concentrations However, CCK promotes reduced food intake via vagus nerve… Human studies with CCK agonists fail to produce weight loss Animal dysbiosis studies demonstrate reduced vagus nerve input to brain resulting reduced CCK-induced satiety Hedonistic Pathways Observations: No direct connection between mesolimbic dopaminergic system (reward system) and gut microbiota has been established, hypothesize that gut dysbiosis may influence via causing generalized neuroinflammation Von Son 2021, Longo 2023 Microbiota-gut-brain axis (MGBA) and GLP-1 Glucagon-like peptide 1 (GLP-1) Released by intestinal epithelial enteroendocrine cells Within the small intestine, this release is induced by presence of specific nutrients Within the large intestine, this release is induced by the microbiota Functions: Increase insulin and reduce glucagon Delay gastric emptying and promote pyloric contractions Regulate appetite (suspected via vagus nerve) Giving butyrate (SCFA) via IV ! no influence on appetite (animal study) BUT via diet ! decreases food intake Longo 2023 Microbiota: Glucose and Insulin Metabolism Human observations: Transplant of microbiota from healthy patients into patients with metabolic syndrome increases insulin sensitivity Intestinal dysbiosis correlates with low grade inflammation in obesity and in insulin resistance Possible mechanism: Gut microbiota induces increase intestinal permeability resulting in LPS and fatty acid leakage and activation of TLR4 ! systemic inflammation Longo 2023 Microbiota: Energy Harvesting Observations – what do we know so far? Obese humans seem to have reduced counts of Bacteriodetes compared to control (though debated in some studies) Germ-free mice are leaner, but once allowed to be colonized increase body fat by 50% and reduce insulin sensitivity Gut microbiome genes present in obese mice and obese humans appear to be involved in energy harvesting: digesting polysaccharides, transport and intracellular metabolism Fecal transplant from obese mice to germ-free mice results in transfer of obese phenotype Greiner 2011 Microbiota: Lipogenesis Additional observations: Increased energy harvest ! increased fermentation ! increased production of short chain fatty acids (SCFA’s) Obese humans have elevated SCFA production Mice deficient in SCFA receptors are leaner than controls Greiner 2011