INTRODUCTION

Obesity is excess body fat frequently resulting in a significant impairment of health. Excess body fat not only leads directly to modern chronic disease, but worsens the severity of exising diseases. These diseases include:

  • Hypertension
  • Osteoarthritis (a degeneration of cartilage and its underlying bone within a joint)
  • Low Back Syndrome
  • Hyperlipidemia
  • Metabolic Syndrome
  • Nonalcoholic Fatty Liver Disease (NFLD)
  • Type 2 diabetes
  • Coronary heart disease
  • Congestive Heart Failure
  • Stroke
  • Gallbladder disease
  • Hernia
  • Sleep apnea and respiratory problems
  • Cancers
    • Endometrial
    • Breast
    • Colon

In addition, a greater number of complications occur in surgery and pregnancy.

In fact, the American Heart Association has now elevated overweight and obesity to risk status for heart attach, stroke, and peripheral artery disease.

BMI exhibits a "J" shaped curve with mortality ratio. That is, very low BMI is associated with an increased risk of mortality. However, high BMI is strongly associated with significantly increasing mortality.

More specifically, most diseases are more associated with the distribution of body fat.

Upper body distribution exhibits a higher incidence of diabetes, independent of degree of obesity.

As is the relationship between hypertension and upper body fat distribution.

What is it in upper body fat that causes these diseases?


INTRAORGAN ADIPOSE DEPOSITS

Excess body fat not only accumlates in subcuteanous or internal deposits. Intraorgan adipose deposits is also a characteristic of excess body fat. Liver, heart and muscle cells are most affected by excess intraorgan fat deposits.

LIVER

Nonalcoholic Fatty Liver Disease (NAFLD) is the most common cause of liver abnormalities and clinical follow-up; including liver transplantation.

Approximately 25-33% of the US population is considered to have NAFLD.

The fat biopsy on the left illustrates excess and enlarged fat cell in the liver; whereas the biopsy on the right is normal hepatic (liver) tissue.

As body fat increases, the intraorgan fat deposits increase similarly in children and adults who are more susceptable to metabolic syndrome and diabetes.

HEART

Lipid accumulation in the cardiac tissue are associated with conduction defects as lipid can accumulate in the SA node, AV node, and right bundle branch. Accumulating lipid deposits can also form irregular aggregates or bands of adipose tissue that separate myocardial cells. These bands interfere with contraction. Cardiac hypertrophy can result from excess fat deposition and/or increased cardiac work associated with ambulating a heavier body weight.

MUSCLE

Excess intramuscular fat deposits are associated with increased lipid metabolism within the muscle.


PATHOPHYSIOLOGY OF ADIPOCYTES

The changes in adipocyte activity can be considered genetic and/or enviromental. Overeating or experimental obesity studies have found that most of these changes can be incuded with deliberate overeating to achieve excess body fat. Do these studies minimize the genetic aspects?

Sims & colleagues compared endocrine and metabolic changes between spontaneous and experimental obestiy and found most of the changes were similar.

As the size of the adipocyte grows in overweight and obesity, the endocrine activities change.

SUBSTANCES
NORMAL WEIGHT
OVERWEIGHT
Leptin
Low
High
Adiponectin
High
Low
TNF-alpha
Low
Very High
IL-6
Low
Very High
Angiotensin
Low
High
Plasminogen activator inhibitor
High
Increased
Resistin
Low
High

Leptin

Although leptin increases in overweight and obesity, it appears to decrease function. For, example, the hypothalamus becomes resistance to leptin. Thus, the signal for satiety is not recognized; neither are the signals for other endocrine functions which affect the

  • Hypothalamic-pituitary-adrenal axis
  • Hypothalamic-pituitary-thyroid axis
  • Hypothalamic-pituitary- gonadal axis

The leptin resistance may be found more in the central nervous system than in the peripheral organs (pancreas, liver & muscle).


Adiponectin

Adiponectin decreases in overweight and obesity. An increase in inflammatory cytokines as well as an increase in insulin resistance may be the initiating factors to decrease adiponectin. The decrease of adiponectin decreases vascular nitric oxide production which decreases endothelial antiatherogenic function.


TNF-alpha

TNF-alpha is primarily secreted from the macrophage in adipose tissue. TNF-alpha activity increases dramatically in overweight and obesity. TNF-alpha action is to increase insulin resistance leading to metabolic syndrome, diabetes, and atherosclerosis associated with overweight.


IL-6

IL-6 is another cytokine secreted from the macrophage in adipose tissue and is elevated in overweight and obesity. Its action is to increase insulin resistance; contributing to metabolic syndrome, diabetes, and atherosclerosis.


Angiotensin

Substances from the renin-angiotensin system (RAS) are increased in overweight and obesity. Angiotensin II is the most active form and is a potent vasoconstrictor in the vasculature. Hypertension is the primary outcome, however, inflammation and endothelial proliferation are also associated with RAS substances in overweight and obesity. The inflammation and hypertension increase the risk for atherosclerosis.


Resistin

The increase in resistin found in overweight and obesity increases insulin resistance, leading to metabolic syndrome, diabetes and atherosclerosis.


PAI-1

PAI-1 is elevated in overweight and obesity. The primary function of PAI-1 is to inhibit the conversion from plasminogen to plasmin. Elevated PAI-1 upsets the balace between thrombotic (clot formation) and fibronolytic (breakdown of fibrin) systems favoring the formation of thrombi in the artery, accelerating the atherogenic process.


 

The pathophysiology of obesity, as it relates to the etiology of atherosclerosis, metabolic syndrome and diabetes is summarized below.

These activities contribute to atherosclerosis, hypertension, metabolic syndrome and type 2 diabetes


OXIDATIVE STRESS IN EXCESS BODY FAT

The adipocyte with excess lipid produces oxidative stress as represented by the increase in TNF-alpha and IL-6.

The figure to the right illustrates higher oxidative stress at rest in obese adults.

Apparenlty healty adults increase oxidative stress during high intensity or maximal exericse (yellow line). Adults who are obese exhibit even more oxidative stress with maximal exericse (red line).

Vincent, MSSE.

On those same lines, any physical activity for overweight and obese individuals will produce more oxidative stress than thier normal weight counterpart.

This elevated oxidative stress has a role in the etiology of cardiovascular disease and cancer.


THE ROLE OF OBESITY IN THE ETIOLOGY OF METABOLIC SYNDROME

Metabolic syndrome is cluster of metabolic abnormalities and cardiovascular risk factors. The outcome of this cluster is cardiovascular diseases and diabetes. These abnormalites include:

  • Glucose intolerance
  • Obesity
  • Hypertension
  • Hyperlipidemia

 

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Diabetes is the extension of Metabolic Syndrome.

 

ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

This atherosclerotic process occurs in most arteries. The following table summarizes the three main forms of this cardiovascular disease. When the atheroma partially blocks the artery, low blood flow or ischemia occurs. When the artery becomes totally blocked the tissue dies. Death of tissue has been termed infarct or necrosis.

Location
Ischemia
Infarct
Coronary Arteries
Angina
Myocardial Infarction
Cerebral Arteries
Transient Ischemic Attack
Cerebral Vascular Accident
Femoral
Claudication
Gangrene

Nitric oxide (NO) is the molecule that protects the artery from developing atherosclerosis. This molecule is found in the innermost layer of the artery; a single cell layer called the endothelium.

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When NO fails to protect the artery, this oxidation/inflammation cycle occurs.

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CANCER

The key to understanding the etiology of cancer is found in the cell cycle of the reproduction of the cell. Those cells that do not reproduce are virtually immune to cancer.

  • Nerve Cells
  • Muscle Cells
  • Myocardial Cells

 

 

An animation of the cell cycle

Those cells with the highest turn-over are more likely to develop cancer. More specifically, the cells with the shortest G1 period are more susceptible to cancer. The G1 phase is the growth period following division. In this phase the cell differentiates into the intended cell.

Approximate Durations of Cell Cycle Periods
 Type of Cell
Duration of Period (hours)
Entire Cycle
G1
S
G2
M
Blood-Forming Marrow
~13
2
8
2
0.7
Ileum
~17
6
8
2
0.7
Duodenum
~18
7
8
2
0.7
Colon
~33
22
8
2
0.7
Tongue
~40
28
8
3
0.7
Esophagus
~181
170
8
2
0.7
Skin
~1,000
989
8
2
0.7
Liver
>10,000
>9,989
8
2
0.7
Mature Nerve, Muscle
Do no divide beyond infancy.

 

All normal cells reproduce and die. The reproduction is genetically controlled so that a new cell replaces an old one of the same kind. The number of cells are controlled so that the organ remains the proper size; not too big or too small. Normal cells differentiate into specialized functions such as red blood cells or skin cells. Essentially, in cancer, a normal cell becomes a cancer cell, which reproduces in an unchecked manor, eventually taking over the normal cells, but not taking over the normal cell function. The organ soon fails as normal function cannot be maintained. As the cancer metastasizes it takes over other organs in a similar manor. If left unchecked, the body cannot maintain various functions and soon dies.
FEATURE
NORMAL CELL
CANCER CELL
Regulation of Reproduction
Controlled
Defective
Transition from G1 to S
Regulated
Poorly Regulated
Differentiation
Normal
Abnormal
LIfe-Span
Die on Schedule
Immortal

Environmental events that contribute to a malfunctioning in the G1 in the normal cell cycle:

  • Chemicals
    • Occupational
      • Chimney Sweeps was the first occupation to find a link between job and scrotal cancer in 1775
      • Asbestos
    • Life-Style
      • Smoking
      • Dietary
        • Smoked, pickled, cured
        • High in nitrates
        • Cooked at high temperatures
        • High Fat
    • Drinking Water
  • Viruses
  • X-Rays
  • Radioactive Materials

Chemicals and/or radioactive material that cause cancer are called carcinogens. A list of known carcinogens, with explanations, can be found at

http://ehp.niehs.nih.gov/roc/toc9.html#toc.

The mechanism of these carcinogens is most likely a modification the cell DNA during G1

For some forms of cancers, genetics plays a significant role. These cancers include:

  • breast - incidence 1 in every 5 people for families with breast cancer, whereas normal incidence is 1 in every 12 people.
  • stomach
  • colon - risk is 20-30 times if colon cancer runs in families
  • uterine
  • prostate
  • lung

The genetic contribution may be found in the immune system. The genetic defect may be the inability to produce the specific antibody or the inability to produce enough antibody to fight the cancer cells. Tumor antigens recognized by T-Cells can be one of four types:

  • antigens encoded by genes explicitly expressed by tumors
  • antigens encoded by deviate forms of normal genes that have been changed by mutation
  • antigens typically expressed at certain stages of differentiation or only by certain differentiation lineages
  • antigens that are expressed in excess by certain tumors

The innate immune system also plays a role in fighting the invading tumor. Natural killer cells, macrophage and neutrophills are increased during times of remission.

In addition, some genetic disorders result in cancer:

 

EXCESS BODY FAT leads to cancer through the oxidative stress produced by the adipocyte. This oxidative stress can damage DNA to mutate the cell. The cancers associated with obesity include:

  • Endometrial
  • Breast
  • Colon

 



STRESS OF EXCESS BODY FAT

Adipose tissue is not dead weight. Adipose tissue is active dynamic tissue. Blood flow to adipose tissue at rest is 2-3 mL/min per 100 grams of adipose tissue; increasing more than ten times during periods of higher metabolic activity. Adipose blood flow increases following a meal.

Excess body weight requires a higher metabolic demand, not only for the adipose tissue, but for the body as a whole. Hemodynamic adjustments to the increased metabolic demands include:

Increasing Variables
Decreasing Variables
  • Total Blood volume
  • Cardiac Output
    • Stroke Volume
  • Myocardial Mass
    • Left Ventricular Hypertrophy
  • Cardiac Dysrhythmias
    • Atrial Fibrillation
  • Systolic Blood Pressure
Peripheral Vascular Resistance

 

How does energy expenditure change during physical activity?

Definitions for energy expenditure:

  • absolute oxygen up take = VO2 (mL/min)
  • relative oxygen uptake = VO2 (mL/min kg)
  • 1 MET = basic unit of metabolism (at rest) = 3.5 (mL/min kg)
  • caloric cost of physical activity is 5 kcal/(L/min) VO2
  • weight dependent activities are weight bearing
  • weight independent activites are non-weight bearning
The relative energy expenditure for various weight dependent activities (wt bearing) activities remains the same (mL/min kg). That is, if walking 3 miles per hour takes 3 METs or 10.5 ml/min kg; and it will remain similar for normal weight and overweight individiuals. The absolute VO2 (mL/min) to achieve the 3 METs, however, will be higher for the overweight individual; because the the body weight will be greater. To produce 3 METs a 50 kg person would have to use 575 mL of oxygen/min whereas a 100 kg person would have to use 1150 mL of oxygen/min.
Weight independent (non weight bearing) work is different. Cycling at 50 Watts requires a similar absolute oxygen uptake requirement (VO2 (mL/min); but the relative oxygen uptake (VO2 mL/min kg) is modified by body weight. Both the 50 and 100 kg individuals require 540 ml/min to ride a bike at 50 Watts. However, because of the body weight, the relative (to body weight) energy expenditure turns out to be 10.8 ml/min kg (3.0 METs) for the 50 kg person and 5.4 ml/min kg (1.5 METs) for the 100 kg person. The non weight bearing activity requires similar absolute (not relative) VO2 the larger person will be performing at a lower VO2 (ml/min kg) relative to body weight because of their excess body weight.

To complicate this further, remember VO2 max will be considerably lower in the overweight or obese individual, which makes the intensity, relative to their max, quite high. Let's say the VO2 max for the 50 kg person is 50.0 ml/min kg (14 METs) and the VO2 max for the 100 kg person is 25.0 ml/min kg (7 METs). The 3 MET requirement for the walking (above) will be 20% for the 50 kg person, but 42% for the 100 kg person. For the cycling, the 50 Watts will be 21% for the 50 kg person, and surprisingly the same 21% for the 100 kg person.


This page was last updated 21-Sep-2010
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