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Leptin | Resistin | TNF | Adiponectin | Others | References Obesity can no longer be regarded simply as a social
disease. Although it has long been known that the major elements
which lead to obesity as a chronic medical condition are both hereditary
and environmental, it is Major patho-physiologic mechanisms are being identified that tie together the disordered clinical manifestations of obesity and its complications. Examples of this include the role of Leptin in both obese and protein calorie-malnutrition states, inflammatory status in the obese individuals and the adipokine connections to vascular disease states, and alterations in energy metabolism (thyroid physiology) associated with altered cytokine physiology (Leptin). The relevance and investigation of these alterations are critical not only to devising new pharmacologic agents to address this altered physiology associated with obesity, but to identify and address more clearly the role lifestyle, diet and exercise to avoid the progressive morbidity and mortality associated with obesity. In the scheme outlined below, several adipokines (adipose cell derived cytokines) are reviewed. The challenge is to identify other relative and connecting peptides and factors and to include them in a broad general mechanistic format.
Leptin It is released based on acute changes in energy intake (eating) and is high following a meal and low in the fasting state. In other words, it stimulates appetite and decreases when a person is fed. Leptin regulates the secretion (release) of several hormones. Included are the gonadotropins (LH & FSH) which regulate fertility and sex steroid production, as well as thyroid releasing hormone and growth hormone. For example, in cases of starvation, as in low food availability, anorexia nervosa or thin body habitus / decreased fat mass (genetic low fat mass, ballet dancers and runners) leptin levels are very low and output of the pituitary hormones that stimulate ovaries and responsible for normal cycling are low. This leads to loss of periods (amenorrhea) and low estrogen. Leptin infused in low weight amenorrheic women restores normal menstrual cycling without increasing body weight and may normalize testosterone levels in men with low body weight/ starvation states. TSH may demonstrate hyporesponsiveness to hypothalamic (TRH) stimulus, and in severe protein calorie malnutrition or chronic wasting states may manifest as low or normal TSH with low or normal FT4 and low levels of T3, characteristic of Sick Euthyroid Syndrome. Growth hormone secretion and growth factor stimulation may be reduced in obese individuals resulting in reductions in cardio-pulmonary function and oxygen consumption. Clinical manifestations include low energy and stamina, poor sleep and mood, and depression. Although leptin deficiency has been recognized in children - a cause of extreme obesity in early years, deficiency of Leptin and derangements in Leptin receptors are responsible for only 2% of obesity in children. Abnormalities in "downstream" or post-receptor defects in leptin activity are responsible for 10% of childhood obesity. Adults generally manifest abnormal Leptin physiology as Leptin resistance, commonly seen in obese adults. Type 2 diabetes is associated with insulin resistance and usually accompanied by Leptin resistance.
Resistin In addition, with respect to endothelial (vascular) activity, Resistin plays a role which is reciprocal to the actions of adipokine, Adiponectin. Expression of Resistin induces the expression of adhesive molecules (VCAMs) residing in the circulation that increases the adhesion of leukocytes to vascular endothelium, and may be the key to small vessel inflammation and atherosclerosis.
TNF Alpha TNF alpha acts with IL-6 in liver cells, increases insulin resistance and increases inflammatory markers. Uncontrolled diabetic females have a higher risk of cardiovascular disease. Risk was 50% higher in those individuals and correlated with both high HbA1c and high TNF alpha compared with low levels of both. Women with high TNF alpha and lower HbA1c were at higher risk than those with the high HbA1c and lower TNF alpha. Adiponectin Others Ciliary Neurotropic Factor (CNTF)- appears to modulate Leptin pathways, leads to weight loss even when Leptin levels are unchanged. Plasminogen Activating Inhibitory Factor (PAI-1)- inflammatory molecule increasing inflammatory reactivity in vascualer bed. Gene is induced by TNF alpha. Angiotensinogen-dual role in genesis of hypertension and increasing fatty acid synthesis in adipocyte. References Click here for full list of references.
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