III.2.B.b. Leptin

Leptin is a polypeptide (encoded by the ob gene) secreted from the adipose tissue (mainly the subcutaneous white adipose tissue), through it is also produced by the stomach, skeletal muscle and placenta. It has a major role in the optimization of the body fat mass. Leptin informs the hypothalamus about the body fat mass. Leptin together with insulin provides the “satiety signal”. Leptin bound to the C-reactive protein (CRP) circulates in the blood. The increased body fat mass secretes more leptin into the blood. Leptin inhibits neuropeptide Y (NPY) and thereby food intake and it increases energy expenditure and regulates the pancreas. The elevated CRP level correlates well with the waist circumference, with the insulin resistance, with the body mass index (BMI) and with the increased blood Glu level.   

            When the body fat mass decreases, the blood leptin concentration decreases. This stimulates the release of NPY from the hypothalamus. Leptin receptors are situated in the hypothalamus, cerebellum, hippocampus, thalamus, kidneys and lungs. 

Main effects: It decreases the production of NPY in the hypothalamus (nucleus arcuatus).

Cholecystokinin (CCK), melanocortin, and glucagon-like peptide-1 (GLP-1) have similar effects.

Pro-opiomelanocortin- and cocaine- and amphetamine-regulated transcript (POMC/CART) is also located in the nucleus arcuatus. Its main effect is the inhibition of food intake and the increase of energy expenditure. Leptin enhances these effects through its receptors found in the neuronal populations of the nucleus arcuatus.

Side-effects:

It inhibits insulin synthesis, but increases the insulin sensitivity of the tissues;

stimulates glucagon synthesis;

increases Glu uptake by the muscles, glycogenesis and GLUT-4 transport synthesis;

increases Glu release from the liver;

increases lipolysis (during the stimulation of a sympathetic effect);

stimulates the immune system and enhances macrophage activation;

increases the production of proinflammatory cytokines IL-6, TNF-α, interleukin-12 (IL-12) and interferon gamma (IFN-γ);

increases the levels of CRP and IL-6 in the liver;

behaves as a vasoconstrictor (through the endothelial leptin receptors) and increases the sympathetic effect in the kidneys and the adrenal glands, thereby increasing the blood pressure;

behaves as an indirect vasodilator; increasing Na⁺ release by the kidneys and NO release by the endothelial cells. 

The fluctuations in its level reflect a circadian rhythm: it has a higher level in the morning and the lowest level in the afternoon.

A low leptin level may cause obesity.

Its release is increased by insulin, glucocorticoids, estrogens and proinflammatory cytokines (e.g. TNF-α).

Its synthesis is inhibited by a lack of insulin, β-adrenergic effects, testosterone, FFA and GH.

Leptin resistance

The blood leptin level is high in obese patients, but it cannot suppress the appetite. The elevated level of leptin produced in the brain prevents the signaling of an increased peripheral level of leptin to the brain. The leptin receptors are covered by proteins such as CRP, and leptin therefore cannot bind to its receptors. Leptin resistance is tissue-specific. It may develop in the hypothalamus, the muscles, the liver or the pancreas, but not in the immune system.