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WEEK 3 Complications of Obesity

WEEK 3 Complications of Obesity. Bonnie Beezhold, PhD, MHS Assistant Professor Benedictine University. Medical Complications of Obesity. Idiopathic intracranial hypertension. Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome. Stroke. Cataracts.

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WEEK 3 Complications of Obesity

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  1. WEEK 3 Complications of Obesity Bonnie Beezhold, PhD, MHS Assistant Professor Benedictine University

  2. Medical Complications of Obesity Idiopathic intracranial hypertension Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome Stroke Cataracts Nonalcoholic fatty liver disease steatosis steatohepatitis cirrhosis Coronary heart disease Diabetes Dyslipidemia Hypertension Severe pancreatitis Gall bladder disease Cancer breast, uterus, cervix colon, esophagus, pancreas kidney, prostate Gynecologic abnormalities abnormal menses infertility polycystic ovarian syndrome Osteoarthritis Phlebitis venous stasis Skin Gout

  3. What is Metabolic syndrome • Cluster of risk factors for atherosclerotic disease: • Abdominal obesity • Insulin resistance • Hypertension • Dyslipidemia (high TGL, low HDL) • Chronic inflammation is a trigger in the pathogenesis Which one is the driver?

  4. Waist Size vs BMI and the Metabolic Syndrome Waist circumference < level 2* Waist circumference > level 2* 33.43 8-y Incidence of Metabolic Syndrome (%) 20.45 19.77 9.98 *Level 2 = waist 40 inches in men or 35 inches in women. Han TS et al. Obes Res. 2002;10:923-931.

  5. Both Insulin Resistance and Decreased Insulin Secretion Predict the Risk of Developing Type 2 Diabetes: 7-Year Incidence Percent NeitherLowHigh Insulin secretionLowLow Insulin resistanceHighHigh BothHighLow Metabolic statusHOMA-IR I30-0min/G30-0min Haffner SM et al. Circulation. 2000;101:975-980.

  6. Relationship Between BMI and Cardiovascular Disease Mortality Men Women Relative Risk of Death Lean Overweight Obese <18.5 18.5–20.4 20.5–21.9 22.0– 23.4 23.5– 24.9 25.0– 26.4 26.5–27.9 28.0– 29.9 30.0– 31.9 32.0–34.9 35.0– 39.9 >40.0 Body Mass index Calle et al. N Engl J Med 1999;341:1097.

  7. Visceral adiposity Central complication of obesity is the development of insulin resistance Link between visceral fat accumulation and insulin resistance (IR), so complications are related to WHERE fat is located, not to how much Associated with dyslipidemia - elevated plasma free fatty acids and triglyceride levels, alteration of lipoproteins http://google.com/

  8. Fat cells are actually highly complex endocrine, inflammatory, and metabolic tissue. http://www.diabetes-warrior.net/

  9. Adipose tissue • Highly protective, prevents ‘ectopic fat’ • Intra-abdominal, visceral fat has limited ability to make new fat cells allowing for healthy expansion of ‘fat pad’ • Increased release of free fatty acids, impaired TGL storage > insulin resistance

  10. The adipocyte Graphics from http://www.indiana.edu/~K536

  11. Adiponectin • Adiponectin is the most prevalent hormone in fat cells • Roles are to stimulate absorption of lipids into AT and to promote fat oxidation and insulin signaling • It is anti-inflammatory and anti-atherogenic

  12. Adiponectin is found at high levels in lean individuals, decreased in obese individuals • Mice that were genetically engineered to overeat and produce high adiponectin were extremely obese but metabolically normal (Kim et al, 2007)

  13. Macrophages Inflammatory cytokines • Fat cell size correlates with obesity and with the degree of macrophage infiltration into AT • Number of macrophages are increased in obese subjects compared with nonobese subjects • Macrophage infiltration contributes to an inflammatory cascade Avram et al, 2005; Weisberg et al, 2003; Cancello et al, 2005; Cinti et al, 2005

  14. TNF-alpha and IL-6

  15. Chronic inflammatory cascade - adipocyte hypoxia and death M1 fractions of macrophages are proinflammatory, M2 fractions suppress inflammation. The balance is altered with obesity.

  16. The humoral and innate immune system is in involved in the chronic inflammation in obese adipose tissue. CD8+ T cells are activated, which interact with macrophages and propagate the inflammatory cascade. Nishimura, 2009

  17. ER stress and apoptosis • In obesity, ER functions are abnormal due to… • excessive demands, leading to production of CHOP (abnormal protein), resulting in reduced adiponectin • excess of unfolded proteins which decreases protein translation leading to apoptosis • Release of more FFA and inflammatory mediators (Ferranti & Mozaffarian, 2008)

  18. Mitochondrion and oxidative stress • Processing of excess FFA causes mitochondrial uncoupling and release of reactive oxygen species • Oxidative stress defined as imbalance in levels of ROS vs reducing agents • Obese individuals have increased malondialdehyde (MDA) and conjugated diene in AT (Furukawa et al, 2004) • Damages cells, adversely affects insulin production, may lead to beta cell apoptosis

  19. Obesity and triglyceride-derived toxic lipid metabolites accumulate in ectopic tissues and lead to multiorgan dysfunction and common chronic metabolic diseases such as NAFLD and to T2DM and CVD. Cusi, 2012

  20. Is hyperplastic obesity inflammatory? • Hyperplasia - adipogenesis • Increased cell size rather than overall obesity is the trigger to macrophage infiltration (Cinti et al, 2005) • Expansion of fat without inflammation may not lead to detrimental metabolic effects (Kim et al, 2007)

  21. Effect of weight loss on C3 and C4 components of complement in obese patients Antonio Hernández-Mijares, 2011 Background  The aim of this study was to evaluate the effects of weight loss on lipid and metabolism parameters and on the levels of C3 and C4 components of complement in obese patients. Design  This is a longitudinal intervention study based on a 6-week very low-calorie diet (VLCD), a liquid formula of 603 kcal/day. A total of 131 middle-aged patients were distributed among grades II, III and IV of obesity. Anthropometric parameters, total cholesterol, TGL, HDLc, LDLc, apolipoproteins A-I and B-100, glucose, insulin, HOMA-IR and C3 and C4 levels were evaluated at baseline and after 6 weeks of intervention. Results  After VLCD, the moderate weight loss was accompanied by a significant reduction in C3 levels in grade III and grade IV patients (10·2% and 15·4%, respectively; P < 0·001). C4 levels were not altered. Adherence to the diet improved anthropometric parameters and was accompanied by a significant decrease in all lipid profile parameters (P < 0·001). In addition, weight loss was associated with a decrease in glucose levels and HOMA-IR (P < 0·01).

  22. Lipoprotein Changes with Weight Loss After 1 Year on Prescribed Diets of Differing Composition LDL, low-density lipoprotein; HDL, high-density lipoprotein. Dansiger ML, et al. JAMA. 2005;293:43-53.

  23. Happy fat? • ~15-20% of people who are obese, some morbidly, are healthy • Some may be genetically able to expand their AT without pathology • Some may have ability to increase subcutaneous AT vs visercal AT • What factors influence where fat is deposited?

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