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Leptin and Obesity

Obesity is characterized by excessive growth of adipocytes (fat cells), which are the primary site for energy storage. Leptin is a 167 amino acid protein, encoded by the obesity (ob) gene. It is expressed mainly in adipocytes: the more fats in the body, the more leptin molecules are produced.

Normally, the production of leptin is to counteract the buildup of fats by at least two different mechanisms: (1) Stimulating energy production and (2) inhibiting appetite.

Regulation of Energy Balance

In a biological system, ATP is the major energy carrier. Hydrolysis of ATP to ADP and then to AMP releases energy. ATP can be produced from the oxidation of free fatty acids. In adipocytes, energy is stored in the form of triglycerides (fats). A triglyceride molecule consists of three fatty acid chains and a glycerol. When the body needs energy (e.g., during exercise), some hormones can activate a hormone-sensitive lipase that is present in large quantity at the fat cell membrane. The activated lipase then causes the breakdown of triglycerides, releasing free fatty acids for the production of ATP. This process will reduce fats.

AMP-activated protein kinase (AMPK) is an important energy regulator. This enzyme is activated by rising AMP concentration (which generally is coupled to falling ATP level). Upon activation, AMPK can turn on ATP-producing pathways (such as fatty acid oxidation and glycolysis) and switch off ATP-consuming pathways (such as lipogenesis). Thus, activation of AMPK has the effect of reducing fats.

Adipocytes can release a class of molecules known as adipokines for the regulation of energy homeostasis (review). This class includes leptin, adiponectin, tumor necrosis factor-α and many others. Both leptin and adiponectin can activate AMPK. In addition, these adipokines are interrelated. For instance, leptin can stimulate adiponectin expression, thereby enhancing the activation of AMPK.

Regulation of Appetite

The appetite is controlled by two types of neurons in the hypothalamus of the brain: NPY/AgRP neurons and POMC/CART neurons. Activation of the NPY/AgRP neurons releases NPY (neuropeptide Y) and AgRP (agouti-related protein), which stimulate appetite. Activation of the POMC/CART neurons releases α-MSH (α-melanocyte-stimulating hormone) and CART (cocaine and amphetamine-regulated transcript), which inhibits appetite. POMC (Pro-opiomelanocortin) is the precursor of α-MSH.

Leptin may circulate through the bloodstream to these neurons and act on its receptors, which relay the signal via the JAK/STAT pathway. In the NPY/AgRP neurons, leptin suppresses the expression of NPY and AgRP, while in the POMC/CART neurons, it enhances the expression of POMC and CART. Therefore, in both sets of neurons, leptin acts to reduce food intake, making the body leaner.

Leptin Resistance

When the normal function of leptin was discovered, researchers thought that leptin might be used to treat obesity. Unfortunately, this is true only for very rare cases caused by defects in leptin or its production. For most obese people, leptin and its production are normal. In fact, since the production of leptin increases with increasing fats, most obese people have high level of leptin, but it does not induce the expected responses. This phenomenon is called leptin resistance.

Leptin resistance is associated with impairment of leptin transport across the blood-brain-barrier or leptin signaling such as reduced leptin receptor activity or leptin receptor blockade. It has been found that SOCS-3 (suppressor of cytokine signaling 3) and STAT3 phosphorylation are involved (review).

Review Articles

Leptin resistance: a prediposing factor for diet-induced obesity - Am J Physiol Regul Integr Comp Physiol., 2009.

Adipokines and Insulin Resistance - Molecular Medicine, 2008.

Targeting AMP-activated protein kinase as a novel therapeutic approach for the treatment of metabolic disorders - Diabetes and Metabolism, 2007.