Pathophysiology of obesity

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A three-dimensional model with two pairs of opposed curling columns attached together at their ends by more linear segments.
A graphic depiction of a leptin molecule

Pathophysiology of obesity is the study of disordered physiological processes that cause, result from, or are otherwise associated with obesity. A number of possible pathophysiological mechanisms have been identified which may contribute in the development and maintenance of obesity.[1]

Research

This field of research had been almost unapproached until the

PYY 3-36, cholecystokinin, adiponectin, as well as many other mediators have been studied. The adipokines
are mediators produced by adipose tissue; their action is thought to modify many obesity-related diseases.

Appetite

Leptin and ghrelin are considered to be complementary in their influence on appetite, with ghrelin produced by the stomach modulating short-term appetitive control (i.e. to eat when the stomach is empty and to stop when the stomach is stretched). Leptin is produced by adipose tissue to signal fat storage reserves in the body, and mediates long-term appetitive controls (i.e. to eat more when fat storages are low and less when fat storages are high). Although administration of leptin may be effective in a small subset of obese individuals who are leptin-deficient, most obese individuals are thought to be leptin resistant and have been found to have high levels of leptin.[4] This resistance is thought to explain in part why administration of leptin has not been shown to be effective in suppressing appetite in most obese people.[1]

While leptin and ghrelin are produced peripherally, they control appetite through their actions on the

ventromedial hypothalamus (VMH), the brain's feeding and satiety centers, respectively.[5]

Arcuate nucleus

The arcuate nucleus contains two distinct groups of

cocaine- and amphetamine-regulated transcript (CART) and has stimulatory inputs to the VMH and inhibitory inputs to the LH. Consequently, NPY/AgRP neurons stimulate feeding and inhibit satiety, while POMC/CART neurons stimulate satiety and inhibit feeding. Both groups of arcuate nucleus neurons are regulated in part by leptin. Leptin inhibits the NPY/AgRP group while stimulating the POMC/CART group. Thus a deficiency in leptin signaling, either via leptin deficiency or leptin resistance, leads to overfeeding and may account for some genetic and acquired forms of obesity.[1]

Immune system

Obesity has been associated with an inflammatory state, which is chronic and low-grade inflammation, known as meta-inflammation.[6][7] Meta-inflammation is subclinical meaning that while there is an increase in circulating pro-inflammatory factors, no clinical signs of inflammation, heat, pain, and redness, are seen with meta-inflammation.[8] Based on the immune system cells involved, both innate and adaptive immunity are involved in meta-inflammation.[8]

There are different types of obesity depending on where fat cells are stored. Abdominal obesity, excess fat cell accumulation in adipose tissue of the abdomen, is associated more strongly with meta-inflammation.[9]

Evolutionarily, adipose tissue has been shown to function as an immune organ.[8] The immune cells located in adipose tissue are important for maintaining metabolic homeostasis. With obesity, the immune cells important for maintaining metabolic homeostasis are suppressed because immune cell function and immune cell amount are affected by excess fat accumulation in adipose tissue.[7][8] Excess fat accumulation can lead to insulin resistance, and insulin resistance has been linked to meta-inflammation.[8] With insulin resistance, there is an increase in macrophages, mast cells, neutrophils, T lymphocytes, and B lymphocytes, and a decrease in eosinophils and some T lymphocytes.[8]

Obesity has also been shown to induce

Hypoxic conditions result from fat cells expanding, and this decreases vascularization to surrounding fat cells.[6][7][8] Decreased vascularization results in decreased amounts of oxygen in adipose tissue so adipose cells have to switch to anaerobic metabolism for energy production.[9] Anaerobic metabolism stimulates inflammation caused by macrophages.[9] There are two types of macrophages, classically activated M1 macrophages that increase inflammation and alternatively activated M2 macrophages that decrease inflammation. In animal studies, obesity has been shown to cause a shift from M2 to M1 macrophages in adipose tissue, causing an increase in inflammation.[7][8][9]

References

  1. ^
    PMID 14744442
    .
  2. PMID 7984236
    .
  3. PMID 7769141
    .
  4. PMID 8886745
    .
  5. ISBN 0-7216-3256-4
    .
  6. ^
    ISSN 2040-1744
    .
  7. ^
    PMID 21633179
    .
  8. ^
    PMID 25006217
    .
  9. ^
    ISSN 1475-2719
    .
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