Leptin, Obesity & Disease

LEPTIN, OBESITY AND DISEASE

Leptin is an adipose tissue produced hormone related to appetite and obesity. Ordinarily increasing levels of leptin suppress appetite and increase energy expenditure. Leptin is also responsible for pubertal development. Interestingly, urinary leptin is higher in prepubertal girls entering puberty than in prepubertal boys entering puberty. At the same pubertal time, follicle stimulating hormone and luteinizing hormone increase. In addition, leptin is directly involved with both growth hormone and prolactin secretion. This endocrine relationship becomes increasingly important later in life, as infertile women have higher levels of leptin than do fertile women. As might be expected, DHEA levels are also lower in individuals as they age and as leptin dysregulation begins. Furthermore, individuals with higher level of leptin are found in overweight individuals, as obese individuals become increasingly resistant to the normal appetite suppressing effects of leptin. Indeed, leptin regulation appears to be modified primarily by hyperinsulinemia and not by hyper or hypoglycemia.

Production of leptin may be genetically or constitutionally set early in life, since higher levels of leptin are correlated with development of type 2 diabetes later in life. Insulin regulation is also closely related to leptin. Individuals with early hyperinsulinemia may initially be resistant to weight gain as leptin levels are also higher and may be suppressing appetite before advanced insulin resistance or diabetes develops. As insulin resistance develops with continuing excess calories or glucose loads, this relationship weakens. One of the main causes of obesity is the metabolic dysregulation that occurs with diets high in fats and sugar and/or high glycemic foods. Such diets increase plasma glucose as well as leptin levels and lead to obesity. Fat without accompanying high glycemic foods is not associated with risk of diabetes but transfats do increase this risk, even without the glycemic load! Thus, whatever the genetic predisposition, leptin’s normal regulatory effect on appetite is disrupted by the high fat plus high glycemic load or even by transfats. Interestingly, alcohol also disrupts the normal effect of leptin, decreasing blood levels of leptin which leads to increased appetite. Indeed, alcohol consumption leads to lower production of leptin in adipose tissue. Interestingly, gastrically produced gherlin, another natural metabolic appetite suppressant, is also reduced after alcohol consumption.

Of course, leptin dysregulation is associated not only with obesity and type 2 diabetes but with the co-morbid diseases of hypertension, cardiovascular diseases and at least the endocrine related cancers such as breast and prostate, as well as colorectal cancer. Interestingly obesity is associated with increased production of estradiol and decreased levels of testosterone. Eventually, the long term overdrive of insulin and leptin ultimately impairs gastric motility (?? possible early diabetic neuropathy) and may in the elderly override the central hypothalamic control system leading to the anorexia seen in some elderly individuals. Conversely, young anorexics have decreased levels of both gherlin and leptin, while constitutionally thin individuals have normal levels of both these appetite regulating hormones.

Many factors lead to leptin disturbances, including disruption of the normal circadian rhythm by stress and insomnia. Leptin dysregulation begins coincident with metabolic syndrome X, leading at least to significant inflammatory diseases, including atherosclerosis, rheumatoid spondylitis, multiple sclerosis, other autoimmune diseases and even to degenerative arthritis, gastroesophageal reflux, cancer, and even dementia! Interlukin-6, tumor necrosis factor and High Sensitivity C-Reactive Protein are all elevated along with Body Mass Index and leptin. Fat tissue is an active organ contributing directly to inflammatory, degenerative and malignant diseases.

Interestingly, some depressed individuals have the double whammy of lower leptin levels, an interesting paradox. Normal levels of leptin and the normal leptin appetite suppressing mechanism are lost, contributing to the great tendency of depression to lead at some point to obesity. Bipolar patients are also vulnerable to development of insulin resistance and this vulnerability may be increased by mood stabilizers, anti-psychotics and even beta blockers. Remarkably, obese individuals also have decreased blood concentrations of tryptophan, further reducing serotonin and depressing mood. Both BMI and leptin concentrations are related to the percentage of body fat.

Abdominal obesity is a much greater factor in the development of many of the inflammatory diseases than is peripheral obesity. Surgical removal of subcutaneous fat decreases leptin concentrations but does not improve insulin sensitivity, suggesting that insulin resistance is an independent aspect of metabolic dysregulation initiated by stress and/or dietary imbalances of fat plus carbohydrate. Individuals who lose weight through dietary restraint and physical exercise have decreased leptin levels as well as decreased insulin resistance and decreased inflammatory and tissue necrosis factors.

The paradoxical finding of higher levels of anandamide and related endocannabinoids, also produced in fat cells, in obese individuals raises the interesting question of whether the anandamide levels produce a more satisfying passivity in individuals who may be depressed with decreased levels of serotonin. Conversely, the bliss effect of anandamide may be significantly blunted in those with low levels of serotonin!

The bottom line appears to be that a majority of individuals develop obesity as a complex reaction to general stress, physical inactivity, excess high glycemic foods, especially when accompanied by fat, by the toxic metabolic actions of transfats, ensuing hyperinsulinemia with subsequent dysregulation of the normal appetite suppressing effects of both leptin and gherlin. Disturbances of tryptophan and serotonin, mood depression, immune suppression and increased inflammation, are all consequences which lead to increases in virtually every known disease.