Pathophysiology of obesity - Rawa Muhsin

This is my presentation about the pathophysiology of obesity, including its genetic causes, environmental/acquired factors, and the underlying mechanisms leading to the complications of obesity.

1. Pathophysiology of obesity Dr. Rawa Muhsin MBChB, ABHS-APath

2. Overview Introduction Genetic factors Environmental (acquired) factors Mechanisms Take-home messages

3. INTRODUCTION

4. Introduction Obesity is simply defined as a BMI of ≥30 kg/m 2 or a total body fat percentage of ≥25% in men and ≥35% in women Obesity is recognized as a disease of body weight regulation Obesity is the result of long-term positive energy balance where energy intake exceeds energy expenditure A positive energy balance leads to the accumulation of adipose tissue and a reduced ability of adipose tissue to assimilate excess calories, causing diversion of lipid to other tissues such as the liver and skeletal muscle

5. Energy balance

6. Measuring your caloric intake You Hey ChatGPT, how many calories are in this meal? ChatGPT [thinking...] Too many!

7. Total daily energy expenditure Resting energy expenditure accounts for 60% and reflects cardiorespiratory work and maintaining transmembrane ion gradients at rest Non-resting energy expenditure accounts for 30% and is due to physical activity Thermic effect of feeding (or diet-induced thermogenesis) accounts for 10%

8. Total daily energy expenditure calculation

9. Energy balance regulation Arcuate nucleus in hypothalamus regulates energy intake and expenditure in response to signals from adipose tissue, gut, and other organs Leptin is the most potent afferent signal regulating body energy stores and is produced mainly by adipocytes Defective hypothalamic PI3K/Akt/mTOR pathway blunts anorexigenic signaling (leptin resistance) Ghrelin is produced in the stomach and duodenum, stimulates GH secretion, and increases food intake Serum ghrelin concentrations increase after diet-induced weight loss Gastric bypass is associated with low serum ghrelin concentrations

10. Feedback mechanisms for control of food intake Stretch receptors in the stomach activate sensory afferent pathways in the vagus nerve and inhibit food intake. Peptide YY (PYY), cholecystokinin (CCK), and insulin are gastrointestinal hormones that are released by the ingestion of food and suppress further feeding. Ghrelin is released by the stomach, especially during fasting, and stimulates appetite. Leptin is a hormone produced in increasing amounts by fat cells as they increase in size. It inhibits food intake. From Hall, J. E., & Hall, M. E. (n.d.). Guyton and Hall Textbook of Medical Physiology: Guyton and Hall Textbook of Medical Physiology (14th ed.). Elsevier Health Sciences.

11. Control of energy balance by two types of neurons of the arcuate nuclei

12. Contributors to obesity Obesity results from the interactions of genetic and environmental risk factors

13. Causal linkages among genetics, environmental effects, physiology, behavior, and energy balance Reproduced from: Speakman JR. Obesity: The integrated roles of environment and genetics. J Nutr 2004; 134(8 Suppl):2090S-2105S, by permission of Oxford University Press. Copyright © 2004.

14. GENETIC FACTORS

15. Genetic classification of obesity From Horwitz, A.; Birk, R. Adipose Tissue Hyperplasia and Hypertrophy in Common and Syndromic Obesity—The Case of BBS Obesity. Nutrients 2023, 15, 3445.

16. Syndromic and monogenic obesity Early-onset severe obesity is predominantly genetic in origin These include syndromes in which obesity is a prominent component, as well as monogenic mutations characterized by severe obesity Targeted therapies can be part of treatment since the abnormal gene and biochemical pathway are known

17. Genetic syndromes with obesity Syndrome Gene Albright hereditary osteodystrophy (pseudohypoparathyroidism type 1a) GNAS1 Alström ALMS1 Bardet-Biedl syndrome* BBS1, others Beckwith-Wiedemann Multiple Carpenter RAB23 Cohen COH1 (VPS13B) Prader-Willi** NDN, SNRPN *Setmelanotide, a melanocortin 4 receptor agonist, is available for the treatment of obesity due to Bardet-Biedl syndrome **Prader-Willi is the most common of these syndromes

18. Prader-Willi syndrome From Cassidy, S., Schwartz, S., Miller, J. et al. Prader-Willi syndrome. Genet Med 14, 10–26 (2012).

19. Bardet Biedl syndrome From Forsythe, E., Beales, P. Bardet–Biedl syndrome. Eur J Hum Genet 21 , 8–13 (2013).

20. Genetic mutations associated with obesity Disorder Gene Leptin deficiency LEP Leptin receptor deficiency LEPR* Leptin dysfunction LEP (LEP p.D100Y) Pro-opiomelanocortin deficiency POMC* Proprotein convertase 1/3 deficiency PCSK1* Melanocortin 4 receptor haploinsufficiency** MC4R Melanocortin 2 receptor accessory protein 2 MRAP2 GNAS mutations GNAS complex locus *Setmelanotide, a melanocortin 4 receptor agonist, is available for the treatment of obesity due to mutations in the POMC, PCSK1, or LEPR (leptin receptor) genes **Most common form of monogenic obesity

21. Leptin melanocortin pathway Leptin melanocortin pathway. Leptin is secreted by adipose tissue and activates leptin receptors (LEPR) in the arcuate nucleus: proopiomelanocortin (POMC) expressing neurons are activated accelerating α- melanocyte stimulating hormone ( α- MSH ), which activates the melanocortin-4 receptor ( MC4R ) allocated in the paraventricular nucleus (PVN), leading to reduced food intake and increased energy expenditure whilst inhibiting the secretion of the MC4R antagonist Agouty-related protein ( AgRP ) by AgRP /NPY . Modified from Chermon , D.; Birk, R. Predisposition of the Common MC4R rs17782313 Female Carriers to Elevated Obesity and Interaction with Eating Habits. Genes 2023, 14, 1996.

22. Genetic basis for common obesity Heritability of adiposity in twin studies ranges from 40-75% Body mass index of adoptees correlates better with that of their biologic parents than their adoptive parents >500 genetic loci have been associated with adiposity traits Body mass index, responses to overfeeding and underfeeding, energy expenditure, food choices, hunger, and satiation have all been shown to be significantly heritable

23. Genetic polymorphisms associated with obesity risk Reproduced from: Loos RJF. The genetic determinants of common obesity-susceptibility. In: Adipose tissue biology. Symonds ME (Ed), New York, Springer 2011. Copyright © 2011; with kind permission from Springer Science + Business Media B.V. A large meta-analysis of 340,000 individuals (82 GWAS and 43 metabochip studies) identified 97 loci accounting for 2.7% of BMI variation Missing heritability gap from 2.7% to 75% due to many variants with small individual effects, gene-gene and gene-environment interactions, and rare variants not detected by GWAS Fifty genetic loci associated with waist-to-hip ratios Genetic contribution to the variation in energy intake estimated at 20-50%

24. Fat mass- and obesity-associated ( FTO ) gene FTO gene (16q12.2) has the strongest genetic association with obesity Primary effect of FTO SNPs is to increase energy intake Shifts adipocytes from energy utilization (beige fat) to energy storage ( white fat ) by decreasing mitochondrial thermogenesis 5x From Yin D, Li Y, Liao X, et al. FTO: a critical role in obesity and obesity-related diseases. British Journal of Nutrition. 2023;130(10):1657-1664.

25. Genetic effects modified by environment Impact higher in more recent birth cohorts compared with the earlier birth cohorts due to earlier life exposure to obesogenic environment (increased food intake, increased sugar-sweetened beverage intake, less physical activity) From Walter S, Mejía-Guevara I, Estrada K, Liu SY, Glymour MM. Association of a Genetic Risk Score With Body Mass Index Across Different Birth Cohorts. JAMA. 2016;316(1):63–69. doi:10.1001/jama.2016.8729

26. ENVIRONMENTAL (ACQUIRED) FACTORS

27. Environmental (acquired) factors Dietary intake Increased average food intake over the past several decades Eating more fat, sugar, proteins, and grains, and eating less fruit, vegetables, and dairy than recommended Sugar-sweetened beverages Ultra-processed foods dysregulate dopamine reward pathways, promoting hedonic overeating Less physical activity and sedentary behaviors (e.g. screen media use) increase the risk of obesity

28. Relationship between food and beverage consumption and weight change From: Mozaffarian D, Hao T, Rimm EB, et al. Changes in diet and lifestyle and long-term weight gain in women and men. N Engl J Med 2011; 364:2392. Copyright © 2011 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

29. Environmental (acquired) factors Shortened nocturnal sleep time , late bedtime, and nightshift work cause a reduction in total daily energy expenditure Due to spending more time in sedentary activities and less time in moderate and vigorous physical activity, activation of brain regions associated with food reward, measured food intake, lower satiety hormone levels, and higher ghrelin levels Smoking cessation is associated with an average weight gain of 2.6 kg, partly due to decreased activation of POMC by nicotine Endocrine disruptors such as bisphenol A and perfluorinated chemicals increase risk of obesity

30. Gut microbiome Gut microbiota-derived short-chain fatty acids (e.g., acetate) modulate appetite hormones (GLP-1, PYY) Obese individuals develop a similar microbiome to that of lean individuals after losing weight (altered Firmicutes to Bacteroidetes ratio), which is reversed with weight regain Individuals with a higher gut Prevotella to Bacteroides ratio lost more weight on a calorie-restricted, high-fiber diet From Zhuang Z, Zhou P, Wang J, Lu X, Chen Y. The Characteristics, Mechanisms and Therapeutics: Exploring the Role of Gut Microbiota in Obesity. Diabetes Metab Syndr Obes . 2023;16:3691-3705

31. Environmental (acquired) factors Adults tend to gradually gain weight between the ages of 20 to 65 Pregnancy and menopause are associated with weight gain (due to reduced energy expenditure and rising FSH in the latter) Maternal obesity increases lifelong obesity risk in the offspring through metabolic programming which includes hypernutritional intrauterine environment, epigenetic alterations , and other mechanisms Breastfeeding has a protective effect

32. Medications causing weight gain Antipsychotics (thioridazine, clozapine, olanzapine, risperidone, lithium) Antidepressants , including tricyclics (amitriptyline, clomipramine, doxepin, imipramine), long-term use of some SSRIs (paroxetine), and monoamine oxidase inhibitors Antiseizure medications (valproate, carbamazepine, gabapentin) Diabetes medications (insulin, sulfonylureas, thiazolidinediones) Reproductive hormones (disputed) Other medications (cyproheptadine, beta blockers, glucocorticoids )

33. Diseases associated with weight gain Hypothyroidism Obesity may also predispose to hypothyroidism Growth hormone deficiency Cushing’s syndrome Causes central adiposity and peripheral muscle wasting Glucocorticoids induce 11-beta-hydroxysteroid dehydrogenase type 1 in visceral fat, enhancing its lipogenic capacity Hypothalamic obesity Injury to ventromedial hypothalamus causes hyperphagia and reduced energy expenditure Can result from tumors (craniopharyngioma), trauma, irradiation, surgery, and increased intracranial pressure

34. MECHANISMS

35. Adipocyte hypertrophy and hyperplasia New adipocytes can differentiate from fibroblast-like preadipocytes at any period of life The development of obesity in adults is accompanied by increased numbers , as well as increased size , of adipocytes An extremely obese person may have as many as four times as many adipocytes, each containing twice as much lipid, as a lean person

36. Hyperplasia and hypertrophy in adipose tissue From Horwitz, A.; Birk, R. Adipose Tissue Hyperplasia and Hypertrophy in Common and Syndromic Obesity—The Case of BBS Obesity. Nutrients 2023, 15, 3445.

37. Adipose tissue dysfunction & inflammation Hypertrophic adipocytes in obesity release pro-inflammatory cytokines (TNF- α, IL-6) and chemokines (MCP-1), recruiting macrophages and creating a chronic low-grade inflammatory state Macrophage polarization shift from M2 (anti-inflammatory) to M1 (pro-inflammatory) amplifies tissue damage and insulin resistance Adipokine imbalance ↑ Leptin (resistance diminishes satiety signaling) ↓ Adiponectin (reduced insulin sensitivity) ↑ Resistin (promotes hepatic gluconeogenesis)

38. Environment state and adipocyte’s changes in normal vs. obese conditions From López-Ortega, O.; Moreno-Corona, N.C.; Cruz-Holguin, V.J.; Garcia-Gonzalez, L.D.; Helguera-Repetto, A.C.; Romero-Valdovinos, M.; Arevalo-Romero, H.; Cedillo-Barron, L.; León-Juárez, M. The Immune Response in Adipocytes and Their Susceptibility to Infection: A Possible Relationship with Infectobesity . Int. J. Mol. Sci. 2022 , 23, 6154.

39. Mitochondrial & metabolic dysregulation Impaired mitochondrial β- oxidation in adipocytes leads to ectopic lipid deposition (liver, muscle) Lipotoxicity from free fatty acids disrupts insulin receptor signaling via serine phosphorylation of IRS-1

40. Adipose tissue dysfunction in obesity From Goossens GH and Blaak EE (2015) Adipose tissue dysfunction and impaired metabolic health in human obesity: a matter of oxygen? Front. Endocrinol. 6:55.

41. Systemic & organ-specific effects Insulin resistance and type 2 diabetes Pro-inflammatory cytokines (TNF- α) and free fatty acids inhibit insulin signaling in liver/muscle via JNK/NF- κ B pathways Cardiovascular disease Endothelial dysfunction: IL-6/CRP reduces NO bioavailability, promoting atherosclerosis RAAS activation: Adipose-derived angiotensinogen ↑ hypertension risk Hepatic steatosis (NAFLD/NASH) Visceral fat lipolysis ↑ free fatty acids flux to liver, driving steatosis and fibrosis via TLR4-mediated inflammation

42. Immunometabolic pathways in adipose tissue homeostasis From Caslin, H.L., Hasty, A.H. Extrinsic and Intrinsic Immunometabolism Converge: Perspectives on Future Research and Therapeutic Development for Obesity. Curr Obes Rep 8, 210–219 (2019).

43. Emerging therapeutic targets Neuroimmune crosstalk Sympathetic neuron-associated macrophages regulate lipolysis via β3- adrenergic signaling Gut microbiome modulation Akkermansia muciniphila supplementation improves gut barrier integrity, reducing endotoxin-induced inflammation Pharmacotherapies GLP-1 agonists (e.g., semaglutide ): Enhance satiety, reduce hepatic gluconeogenesis Dual agonists (e.g., tirzepatide : GLP-1/GIP) show synergistic weight loss effects Bariatric surgery : Rapidly ↓ ghrelin and ↑ GLP-1/PYY, normalizing hypothalamic signaling

44. Weight loss and regain dilemma Energy intake and expenditure are coupled at usual weight to oppose sustained alterations in adiposity Energy intake and expenditure are uncoupled with weight loss to promote weight regain via hyperphagia and hypometabolism The energy balance required to maintain the reduced weight is more than the levels required in those who are "naturally" at the same weight Leptin levels decrease after weight loss, and repletion partially reverses hypometabolism during maintenance of weight loss

45. TAKE-HOME MESSAGES

46. Take-home messages Genetic contributions to obesity can be syndromic, monogenic, or polygenic Environmental /acquired factors include dietary intake, exercise and sedentary states, sleep, drugs, diseases, and others Obese adipocytes induce a state of chronic low-grade inflammation causing insulin resistance, ectopic lipid deposition, and various other complications Weight loss is often followed by weight regain due to distorted energy balance (hypometabolism and hyperphagia)

47. The End