Metabolic consequences of obesity

By dr reena singh,jr 1

WHAT IS APPETITE??• Appetite is a complex process that results

from the integration of multiple signals at the hypothalamus. The hypothalamus receives neural signals, hormonal signals such as leptin, cholecystokinin (CCK) and ghrelin and nutrient signals such as glucose, free fatty acids, amino acids and volatile fatty acids

Hormonal circuits from the gut (stomach, small intestine, and pancreas) and fat (adipose tissue) that impact the sensations of hunger and satiety that are exerted via hypothalamic neuroendocrine pathways.

Ghrelin from the stomach, leptin from adipose tissue, insulin from the pancreas, and peptide tyrosine tyrosine (PYY) from the small intestine bind to receptors on orexigenic and/or anorexigenic neurons in the ARC of the hypothalamus.

The effects of these peptide hormone-receptor interactions are release of either the orexigenic neuropeptides NPY and AgRP or the anorexigenic neuropeptides CART and the POMC-derived peptide α-MSH

Excess energy is stored as fat in adipocytes, which expand until the fat is used for fuel.

THE FAT CELLS/ADIPOCYTES

Lipid Droplet

Nucleus

Mitochondria

Brown Fat White Fat

Factors Secreted by Adipocytes

Leptin

Resistin

Adiponectin

The major role of LEPTIN in body weight regulation is to signal satiety to the hypothalamus and, thus, reduce dietary intake and fat storage while modulating energy expenditure and carbohydrate metabolism to prevent further weight gain.

Neuropeptide Y (NPY) Stimulates Feeding

Food Intake

NPYLeptin

Adipocytes

A Model for How Leptin Regulates NPY

ADIPONECTIN• Type of cytokine having anti-inflammatory

and cardioprotective effects

• Adiponectin increases insulin sensitivity

RESISTIN• INCREASES LAVEL OF LDL.• BAD EFFECTS

Larger Higher rate of fat turnover Hormonally more responsive Substances released from abdominal fat

are absorbed via the portal vein and, thus, have direct access to the liver.

Fatty acids taken up by the liver may lead to insulin resistance and increased synthesis of triacylglycerols, which are released as VLDL.

Abdominal fat Cells

What is obesity???• Obesity is defined as a physical condition

in which an individual has a body mass index (BMI) ≥30kg/m2

ASSESSMENT OF OBESITY

BMI = (weight [kg]) / (height [m])2.

Body mass index (BMI) or Quetelet index

Body mass index (BMI)• The BMI is a measure of the relationship

between an individuals weight and height. The BMI is calculated by dividing a persons weight in kilograms by the square of their height in meters. The medical utility for determining a persons BMI is that this measure describes the body weight relative to height and it thus, strongly correlates with the total body fat content in adults

BMI(kg/m2) 19 20 21 22 23 24 25 26 27 28 29 30 35 40

Height(in) Weight (lb)

58 91 96 100 105 110 115 119 124 129 134 138 143 167 191

59 94 99 104 109 114 119 124 128 133 138 143 148 173 198

60 97 102 107 112 118 123 128 133 138 143 148 153 179 204

61 100 106 111 116 122 127 132 137 143 148 153 158 185 211

62 104 109 115 120 126 131 136 142 147 153 158 164 191 218

63 107 113 118 124 130 135 141 146 152 158 163 169 197 225

64 110 116 122 128 134 140 145 151 157 163 169 174 204 232

65 114 120 126 132 138 144 150 156 162 168 174 180 210 240

66 118 124 130 136 142 148 155 161 167 173 179 186 216 247

67 121 127 134 140 146 153 159 166 172 178 185 191 223 255

68 125 131 138 144 151 158 164 171 177 184 190 197 230 262

69 128 135 142 149 155 162 169 176 182 189 196 203 236 270

70 132 139 146 153 160 167 174 181 188 195 202 207 243 278

71 136 143 150 157 165 172 179 186 193 200 208 215 250 286

72 140 147 154 162 169 177 184 191 199 206 213 221 258 294

73 144 151 159 166 174 182 189 197 204 212 219 227 265 302

Below 18.5 Underweight18.5 – 24.9 Normal25.0 – 29.9 Overweight

Monitor for risk

Preobese

30.0 - 34.9 Mod. ObeseIncreased health risk

Obese Class 1

35.0 – 39.9 Severe Obese Obese Class 2

40.0 and above Very Severe obese (Morbid obesity) Major health risk

Obese Class 3

classification

BMI Category

Waist less than or equal to 40 in. (men) or 35 in.

(women)

Waist greater than 40 in. (men) or 35

in. (women)

18.5 or less underweight N/A N/A

18.5 - 24.9 normal N/A N/A

25.0 - 29.9 overweight increased risk high risk

30.0 - 34.9 obese high risk very high risk

35.0 - 39.9 obese very high risk very high risk

40 or greater extremely obese extremely high risk extremely high risk

A given BMI range with the risk for cardiovascular disease and atherosclerosis.

VARIOUS OTHER INDICES

Anthropometry (skin-fold thickness) W/H Ratio & waist circumf. Densitometry (underwater weighing) CT MRI Electrical Impedence

• In recent years..the ratio between waist and hip sizes

• For men <0.9• For women <0.85• Is considered more effective than BMI

Gynoid fat distribution “Pear-shaped” or “lower body” obesity

Waste : hip ratio < 0.8 for women and <1.0 in men.

Encouraged by estrogen and progesterone

Less health risk than upper-body obesity

After menopause, upper-body obesity appears

“Apple-shaped” or “upper body” obesity

Waste : hip ratio > 0.8 for women and >1.0 in men.

Associated with risk of heart disease, HTN & Type II Diabetes

Abdominal fat is released right into the liver

Encouraged by testosterone and excessive alcohol intake

Android fat distribution

TOTAL CHOLESTEROL

<200 mg/dl

• 200-239mg/dl

• >/-240mg/dl

• Desirable

• Borderline high

• high

HDL CHOLESTEROL

• <40mg/dl

• >/-60mg/dl

• Low

• high

LDL CHOLESTEROL

• <100 mg/dl• 100-129mg/dl• 130-159mg/dl• 160-189mg/dl• >/-190

• Optimal• Near optimal• Borderline high• High• Very high

Etiology of Obesity

What leads to obesity????

– Genetic predisposition– Environmental factors– Socialization– Age– Sex– Race– Economic status– Psychological– Cultural– Emotional– Cessation of smoking

Obesity Genes

Gene Gene Product

In Human In Rodent

Lep(ob) Leptin Yes YesLepR Lep.

RecepYes Yes

POMC Propriomelanocortin

Yes Yes

MC4R MSH recep4

Yes Yes

AgRP agoutiRP No Yes

PC-1 Prohor Convrtase 1

Yes No

COMPLICATIONS OF OBESITY

Infertility Depression Obstructive sleep

apnea Gallstones Fatty liver Stress incontinence Venous ulcers Cancer Sudden death

Diabetes Endocrine diseases Coronary Heart

Disease High Blood Pressure Hypertrophic

Cardiomyopathy Stroke Arthritis Gastroesophageal

reflux High cholesterol

METABOLIC SYNDROME

• The combination of abdominal obesity, hyperlipidemia, IR, pro-inflammatory status, and hypertension is clinically referred to as the Metabolic Syndrome

Obesity and Development of the Metabolic Syndrome• A little more than 20 years ago Dr. Gerald

M. Reaven put forth the concept that the insulin resistance syndrome was the root cause of glucose intolerance, elevated LDL along with reduced HDL, and hypertension.

• This clinical concept has evolved into what is now referred to as the metabolic syndrome

• Although obesity, ectopic fat accumulation, and an inflammatory status are central to the pathology of MetS, not all obese individuals develop MetS and not all individuals with MetS are obese.

• • MetS has a multi-factorial etiology that involves a

series of complex interactions between a particular individuals dietary habits, hormonal status, and genetic background.

• The metabolic syndrome, MetS (also once referred to as Syndrome X), is a disorder that defines a combination of metabolic and cardiovascular risk determinants.

• These risk factors include insulin resistance, hyperinsulinemia, central adiposity (obesity associated with excess fat deposits around the waist), dyslipidemia, glucose intolerance, hypertension, pro-inflammatory status, and microalbuminemia.

• The hallmark feature of MetS is indeed insulin resistance.

Criteria set forth by the American Heart Association and the National Heart, Lung and Blood Institute as defining the metabolic syndrome.

• elevated fasting blood glucose

• elevated waist circumference

• elevated triglycerides

• reduced HDL cholesterol (HDLc)

• elevated blood pressure

• ≥ 100 mg/dL (≥ 5.6mmol/L)

• ≥ 102 cm (≥ 40 inches) in men≥ 88cm (≥ 35 inches) in women

• ≥ 150mg/dL (≥ 1.7mmol/L)

• < 40mg/dL (< 1.03mmol/L) in men < 50mg/dL (< 1.3mmol/L) in women

• ≥ 130mm Hg systolic/ ≥ 85mm Hg diastolic

Defining Criteria Parameters of Criteria

Other clinical abnormalities associated with metabolic syndrome

• Non-alcoholic fatty liver disease (NAFLD)

• atherosclerosis

• oxidative stress

• polycystic ovary syndrome (PCOS).

•

A clustering of atherosclerotic cardiovascular disease risk factors that include visceral adiposity (obesity), insulin resistance, low levels of HDLs and a systemic proinflammatory state.

There are key components to the metabolic syndrome which include in addition to insulin resistance (the hallmark feature of the syndrome), hypertension, dyslipidemia, chronic inflammation, impaired fibrinolysis, procoagulation and most telling central obesity

Insulin resistance underlies the cardiovascular pathologies of the metabolic syndrome.

One primary reason for this is the role of insulin in fat homeostasis.

The major role of insulin is to induce the storage of fuel. This can be as fat (triacylglycerides, TGs) in adipose tissue or as carbohydrate in the form of glycogen in liver and skeletal muscle.

• The effect of insulin resistance at the level of fat homeostasis is an increase in circulating TGs, referred to as dyslipidemia.

• Due to insulin resistance there is an increase in the delivery of peripheral fatty acids to the liver which in turn drives hepatic TG synthesis.

• These TGs are then packaged into lipoprotein particles termed VLDLs (very low density lipoproteins) which are returned to the circulation

• . In platelets, insulin action leads to an increase in endothelial nitric oxide synthase (eNOS) activity that is due to its phosphorylation by AMPK.

• Activation of NO production in platelets leads to a decrease in thrombin-induced aggregation, thereby, limiting the pro-coagulant effects of platelet activation.

• This response of platelets to insulin function clearly indicates why disruption in insulin action is a major contributing factor in the development of the metabolic syndrome

• Although MetS is not exclusively associated with type 2 diabetes and the associated insulin resistance, the increasing prevalence of obesity and associated development of type 2 diabetes places insulin resistance as a major contributor to the syndrome.

GENETIC FACTORS IN METABOLIC SYNDROME

• Overfeeding of the mother during fetal development as well as excessive nutritional intake by the mother during the pre-weaning period of postnatal development results in increased obesity, adipocyte hypertrophy, reduced activity, insulin resistance, elevated blood pressure, endothelial cell dysfunction, and altered cardiovascular and renal function in offspring

• . When mothers are obese and fed high-fat diets during fetal development their adult offspring exhibit impaired glucose tolerance, hyperinsulinemia, dyslipidemia, hypertension, resistance to the anorexic actions of the leptin on the hypothalamus, and develop NAFLD.

Treatment and prevention

Weight Management

Energy Balance

Energy Intake Energy Expenditure

Generic/Brand Name Usual Dose Mechanism of Action Side Effects

• Orlistat/Xenical

• Sibutramine/Meridia

• Phentermine/ Adipex, Fastin, Ionamin and others

120 mg with each meal

5-15 mg/d

15-37.5 mg per day as a single or split dose

Peripheral: Blocks absorption of about 30% of consumed fat

Central: Inhibits synaptic reuptake of norepinephrine and serotonin

Central: Stimulates release of norepinephrine

GI symptoms (oily spotting, flatus with discharge, fecal urgency, oily stools, incontinence)

Dry mouth, constipation, headache, insomnia, increased blood pressure, tachycardia

CNS stimulation, tachycardia, dry mouth, insomnia, palpitations

CAUTION//CONTRAINDICATION Pregnancy or lactation Unstable cardiac disease Uncontrolled hypertension (SBP >180, DBP > 110

mmHg) Unstable severe systemic illness Unstable psychiatric disorder or history of anorexia Other drug therapy, if incompatible (eg MAO

inhibitors, migraine drugs, adrenergic agents, arrhythmic potential)

Closed angle glaucoma (caution)

Initial human trials with recombinant leptin were modestly successful. Most subjects in the initial trial developed local reactions at the injection site

.Weight loss was relatively modest.

However, the hormone needs to be given subcutaneously and has a short half-life.A modified recombinant human leptin (m-leptin) was created that has a longer half-life.

Leptin

SURGERY Bariatric surgery – weight loss surgery for severely obese people (BMI > 40)  2 most common approaches

o reducing the volume of the stomach (e.g. by adjustable gastric banding and vertical banded gastroplasty), which produces an earlier sense of satiation.

o reducing the length of bowel that comes into contact with food (gastric bypass surgery), which directly reduces absorption.

THANK YOU