WEEK 3 Complications of Obesity

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WEEK 3 Complications of Obesity

• Bonnie Beezhold, PhD, MHS
• Assistant Professor
• Benedictine University

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Medical Complications of Obesity
Idiopathic intracranial hypertension
Pulmonary disease abnormal function obstructive
sleep apnea hypoventilation syndrome
Stroke
Cataracts
Nonalcoholic fatty liver disease steatosis steatoh
epatitis 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
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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?
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Waist Size vs BMI and the Metabolic Syndrome
Waist circumference lt level 2 Waist
circumference gt 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. 200210923-931.
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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. 2000101975-980.
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Relationship Between BMI and Cardiovascular
Disease Mortality
Men Women
Relative Risk of Death
Lean
Overweight
Obese
lt18.5
18.520.4
20.521.9
22.0 23.4
23.5 24.9
25.0 26.4
26.527.9
28.0 29.9
30.0 31.9
32.034.9
35.0 39.9
gt40.0
Body Mass index
Calle et al. N Engl J Med 19993411097.
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Visceral adiposity
http//google.com/

• 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

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

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The adipocyte
Graphics from http//www.indiana.edu/K536
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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

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• 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)

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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
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TNF-alpha and IL-6
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Chronic inflammatory cascade - adipocyte hypoxia
and death
M1 fractions of macrophages are proinflammatory,
M2 fractions suppress inflammation. The balance
is altered with obesity.
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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
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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)
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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

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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
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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)

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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 (102 and 154,
respectively P lt 0001). 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 lt 0001). In addition, weight loss
was associated with a decrease in glucose levels
and HOMA-IR (P lt 001).
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Lipoprotein Changes with Weight Loss After 1 Year
on Prescribed Diets of Differing Composition
Variable Atkins(n40) Zone(n40) Weight Watchers(n40) Ornish(n40)
Weight (kg) -3.9 (6.0) -4.9 (6.9) -4.6 (5.4) -6.6 (9.3)
LDL Cholesterol (mg/dL) -13.5 (32) -18.1 (41) -14.2 (32) -25.2 (20)
HDL Cholesterol (mg/dL) 6.4 (8.8) 5.1 (12.5) 5.2 (12) -1.1 (9.3)
Triglycerides (mg/dL) -2 (117) 4 (183) -20 (75) 11 (53)
Diet Goals lt20-50 gmcarbs/day 30 fat 30protein 40 carbs 1200-1600cal/day Vegetarianlt10 fat
1-Year Median 190 gmcarbs 37 fat 21protein 39 carbs 1832 cal/day 32 fat
LDL, low-density lipoprotein HDL, high-density
lipoprotein.
Dansiger ML, et al. JAMA. 200529343-53.
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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?