This document discusses metabolic consequences of obesity and the metabolic syndrome. It defines appetite, hormones that regulate hunger and satiety, and how excess calories are stored as fat. Factors secreted by fat cells like leptin, resistin, and adiponectin are described. Obesity is defined as BMI over 30 kg/m2 and methods for assessing obesity are provided. Genetic and environmental factors that can lead to obesity are listed, along with complications of obesity such as diabetes and heart disease. The metabolic syndrome is characterized as a clustering of risk factors including abdominal obesity, insulin resistance, dyslipidemia, and hypertension.

1. Metabolic consequences
of obesity
By dr reena singh,jr 1

3. 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

4. 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

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

7. THE FAT CELLS/ADIPOCYTES
Lipid Droplet
Nucleus
Mitochondria
Brown Fat White Fat

9. Factors Secreted by Adipocytes
Leptin
Resistin
Adiponectin

10.  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.

11. Neuropeptide Y (NPY) Stimulates Feeding

12. Food Intake
NPYLeptin
Adipocytes
A Model for How Leptin Regulates NPY

14. ADIPONECTIN
• Type of cytokine having anti-inflammatory
and cardioprotective effects
• Adiponectin increases insulin sensitivity

15. RESISTIN
• INCREASES LAVEL OF LDL.
• BAD EFFECTS

16.  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

17. What is obesity???
• Obesity is defined as a physical condition
in which an individual has a body mass
index (BMI) ≥30kg/m2

18. ASSESSMENT OF OBESITY

19. BMI = (weight [kg]) / (height
[m])2.
Body mass index (BMI)
or Quetelet index

20. 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

21. 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

22. Below 18.5 Underweight
18.5 – 24.9 Normal
25.0 – 29.9 Overweight
Monitor for risk
Preobese
30.0 - 34.9 Mod. Obese
Increased
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

23. 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.

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

25. • In recent years..the ratio between waist
and hip sizes
• For men <0.9
• For women <0.85
• Is considered more effective than BMI

26. 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

27.  “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

29. TOTAL CHOLESTEROL
<200 mg/dl
• 200-239mg/dl
• >/-240mg/dl
• Desirable
• Borderline high
• high

30. HDL CHOLESTEROL
• <40mg/dl
• >/-60mg/dl
• Low
• high

31. LDL CHOLESTEROL
• <100 mg/dl
• 100-129mg/dl
• 130-159mg/dl
• 160-189mg/dl
• >/-190
• Optimal
• Near optimal
• Borderline high
• High
• Very high

32. Etiology of Obesity

33. What leads to obesity????
– Genetic predisposition
– Environmental factors
– Socialization
– Age
– Sex
– Race
– Economic status
– Psychological
– Cultural
– Emotional
– Cessation of smoking

35. Obesity Genes
Gene Gene
Product
In Human In Rodent
Lep(ob) Leptin Yes Yes
LepR Lep.
Recep
Yes Yes
POMC Propriome
lanocortin
Yes Yes
MC4R MSH
recep4
Yes Yes
AgRP agoutiRP No Yes
PC-1 Prohor
Convrtase
1
Yes No

37. 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

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

39. 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

40. • 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.

41. • 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.

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

43. • 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

44. Other clinical abnormalities
associated with metabolic
syndrome
• Non-alcoholic fatty liver disease (NAFLD)
• atherosclerosis
• oxidative stress
• polycystic ovary syndrome (PCOS).
•

46. 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

49. 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.

50. • 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

51. • . 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

52. • 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.

56. GENETIC FACTORS IN
METABOLIC SYNDROME

57. • 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

58. • . 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.

60. Treatment and prevention

61. Weight Management
Energy Balance
Energy Intake Energy Expenditure

62. 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

63. 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)

64. 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

65. 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.

66. THANK YOU