Leptin is a 167 amino acid protein involved in an endocrine circuit that regulates energy homeostasis. The importance of leptin in energy regulation was not appreciated until 1994, when studies involving ob/ob and db/db genetic mouse strains were performed. These mice were morbidly obese, hyperphagic and had approximately a 3-fold increase in body weight and a 2-fold increase in appetite over genetically normal wild type mice. Experimentation revealed that the ob/ob mice lacked a hormonal factor, which resulted in a failure in the appetite and energy regulation of the animals. The hormonal factor missing from ob/ob mice was discovered to be leptin, injection of which returned their body weight to that of normal mice. However, injection of leptin into db/db mice showed no effect, and cloning of the mutant gene revealed a defect in the receptor that recognised the leptin molecule.
Leptin acts as an afferent signal in a negative feedback loop that regulates adiposity in mammals. Increased circulating levels of leptin cause decreased energy intake, increased energy expenditure, both of which cause weight loss. In contrast, low levels of leptin result in hyperphagia, the conservation of energy, and down-regulation of reproductive function, all of which cause weight gain. The absence of circulating leptin in ob/ob mice, as well as the absence of a functioning receptor in db/db mice, results in a perceived state of perpetual starvation. Humans subjects with a genetic defect in the leptin gene have also responded to leptin administration with dramatic weight loss. However, the cases of genetic defects of leptin production in humans is very rare and confined to a handful of cases in the medical literature.
Leptin activates receptors in the hypothalamus to cause the release of the anorexigenic peptides proopiomelanocortin and corticotrophin releasing hormone (amphetamine and cocaine related transcripts) and also inhibits the orexigenic peptides neuropeptide Y and agouti related peptide. These peptide interact with other brain areas and peripheral sites (such as the gut) to regulate appetite and energy expenditure. Leptin is released from white adipose tissue, with the amount released being proportional to the fat mass present. As adipose tissue accumulates, leptin levels in plasma rise, and this in turn activates hypothalamic receptors to reduces energy intake and increases energy expenditure. Obese subjects appear to have increased levels of leptin, but it is not to be able to regulate energy balance. Evidence suggests that this is due to receptor insensitivity to the circulating leptin.
Recent evidence suggests that the metabolic changes associated with leptin are not solely as a result of its anorexic effects. It is known that ob/ob mice forced to consume the same energy intake as wild type mice are still unable to lose their morbid obesity. In addition, leptin administered to ob/ob mice cause a reduction in fat mass, whereas food restriction causes the loss of fat mass and lean body tissue. Leptin is also able to cause hypophagia, without a compensatory decrease in resting energy expenditure. Leptin insensitivity in humans and leptin deficient mice also accumulate fat in other areas apart from adipose tissue, such as the liver, muscles and other organs. This accumulation of triglycerides in organs, particularly in the liver is a major contributor to the detrimental heath effects of obesity, including non-alcoholic fatty liver disease (NAFLD) (here).
The ability of leptin to remove fatty acids from their storage regions in peripheral tissue, organs and adipose tissue, suggests a unique mechanism of action for leptin. Leptin administration reduces the NAFLD seen in ob/ob mice and reduces associated pathologies. Evidence suggests that leptin may regulate expression of stearoyl-CoA desaturase-1 (SCD-1), a key enzyme in fatty acid metabolism localized in the endoplasmic reticulum. Steroyl-CoA desaturase-1 can use both dietary or endogenously produced saturated fatty acids as a substrate to produce monounsaturated fatty acids (MUFA) by incorporation of a double bond in the ∆9 position. These MUFA are the most abundant fatty acids in triglycerides, cholesterol esters and phospholipids. The fate of the MUFA is to be partitioned into storage in the liver, or to be packaged into very low density lipoproteins and exported to peripheral tissues for storage in muscle or adipose.
Leptin may repress expression of SCD-1, preventing the conversion of saturated fatty acids into MUFA. This causes an accumulation of fatty acyl-CoA molecules which inhibits the enzyme acetyl-CoA carboxylase and thus decreases the conversion of acetyl-CoA to malonyl‑CoA. Falling levels of malonyl-CoA then remove the inhibiting effect of malonyl‑CoA on the enzyme carnitine parmitoyl transferase-1 (CPT-1), which causes an increase in the transport of saturated fatty acids across the inner mitochondrial membrane for β-oxidation. In addition, the fall in malonyl-CoA would decrease further fatty acid synthesis. Leptin may therefore decrease expression of SCD-1 which partitions fatty acids towards oxidation. If leptin levels fall, SCD-1 expression increases which partitions fatty acids towards storage. Stearoyl-CoA desaturase-1 therefore appears to be a key metabolic control point in the utilisation of fatty acids and appears to be under control, at least in part, by leptin.
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