Physiology, Leptin

Cellular Level

Biology

Leptin is a peptide hormone synthesized by white adipose tissue. The leptin gene (LEP or ob) is on chromosome 7q31.3.[2]  The mature protein is comprised of 146 amino acids and produced through mRNA-directed protein synthesis.[3] Its structure is like the proinflammatory cytokines found throughout the body, such as interleukin 6 and granulocyte colony-stimulating factor.[4] The amount of leptin in the blood is directly proportional to the amount of adipose tissue. Leptin exerts its actions by binding to leptin receptors (LR) on the surface of cells. Leptin receptors are present on neuronal, hepatic, pancreatic, cardiac, and intestinal tissue.

Mechanism

The LR belongs to the glycoprotein 130 family of cytokine receptors and comprises 6-isoform. Of these isoforms, isoform-b is the most characterized. Its long-form is the receptor subtype that principally mediates the activation of critical second messenger pathways and normal leptin action.[5] The main signaling pathway for the LR is the JAK-STAT pathway. As leptin binds it to dimerize the LR. This dimerization leads to JAK2 tyrosine kinase phosphorylating three tyrosine residues that serve as docking sites for the proteins SHP2, STAT5, and STAT3. The function of SHP is to participate in ERK signaling, and the function of STAT 5 is as yet undetermined. STAT 3 acts as a transcription factor responsible for mediating leptin’s primary actions. 

Function

Leptin's principal site of action is the brain, specifically in the brainstem and hypothalamus. The major sites of action in the brainstem are the solitary tract and the ventral tegmental area. Leptin acts here to modulate satiety and the control of reward and aversion. In the hypothalamus, the lateral hypothalamic area and the ventromedial, dorsomedial, ventral pre mammillary, and arcuate (ARC) nuclei are leptin’s major sites of action. The activation of these areas leads to various changes, including in the thyroid, gonadal, adrenocorticotropic hormone-cortisol growth hormone axes, and changes in whole-brain cognition, emotions, memory, and structure. Many of these relationships are still being worked out.[6][7] The most well-known of them is leptin’s actions on the ARC nucleus. The ARC nucleus is a major player in regulating appetite and energy homeostasis. It contains orexigenic agouti-related protein/neuropeptide Y-containing (AgRP/NPY) neurons and anorexigenic proopiomelanocortin-containing (POMC) neurons. Leptin acts on the ARC nucleus by stimulating POMC-containing neurons and inhibiting AgRP/NPY containing neurons- having the total effect of decreased appetite.

Taken as a whole, leptin’s function in the body pertains to regulating the balance between food intake and energy expenditure. The classic primary physiologic role of leptin is to serve as a marker of long-term energy stores for the central nervous system (CNS).[8] As the amount of adipose tissue decreases, the amount of leptin produced and crossing the blood-brain barrier decreases. The CNS interrupts the decline in leptin as a signal of energy deficit, which triggers a cascade of responses to help the body deal with the stress of starvation. To counteract the energy deficit, the CNS increases hunger while also promoting energy-sparing neuroendocrine and autonomic mechanisms, including decreased sympathetic nervous system tone, thyroid, and reproductive hormone levels, energy expenditure, and growth. As this signal, leptin is the catalyst for the body's transition into a starvation mode, a global adaption aimed towards increasing food intake and decreasing energy expenditure. A decrease in serum leptin then is the starvation signal for the CNS. As food intake increases and the level of adipose tissue becomes excessive, there is a concurrent rise in the production and secretion of leptin into the bloodstream. With increased leptin comes an inhibition of the body’s starvation mode, thereby promoting reduced food intake and increased energy expenditure to counteract the current energy surplus.

Clinical Significance

Leptin deficiency or resistance is associated with dysregulation of cytokine production, increased susceptibility to infections, autoimmune disorders, malnutrition, and inflammatory responses.

Pathophysiology and Clinical Relevance

Hypoleptinemia

Complete leptin deficiency results in the clinical phenotypes of severe obesity, impaired satiety, intensive hyperphagia, constant food-seeking behavior, recurrent bacterial infections, hyperinsulinemia, liver steatosis, dyslipidemia, and hypogonadotropic hypogonadism.[9][10] These phenotypes highlight the variety of roles leptin has in the body, many not well understood and still actively under investigation. Congenital forms of hypoleptinemia result from mutations in LEP or the LR gene and are known as congenital leptin deficiencies (CLD). Acquired hypoleptinemias share some of these same phenotypes and are usually due to conditions that cause a low body weight. Examples of acquired conditions are lipodystrophy syndromes and hypothalamic amenorrhea.

Hyperleptinemia

Hyperleptinemia is associated with leptin resistance - specifically resistance to the anorectic and body weight-reducing effects of leptin. Hyperleptinemia and leptin resistance are components of common obesity. Evidence for this association is a direct correlation between serum leptin concentrations and body fat percentage where obese individuals had higher leptin serum levels and adipocyte LEP mRNA content compared with normal-weight individuals. Also, leptin serum levels and adipocyte LEP mRNA content fall with weight reduction. The mechanism of resistance appears related to defects in leptin transport across the blood-brain barrier or intracellular signaling mechanisms downstream of the LR. Other diseases associated with hyperleptinemia include nonalcoholic fatty liver disease, Rabson–Mendenhall syndrome, neurodegenerative disorders, depression, and food addiction.[11]

Therapeutics

Recombinant forms of leptin are under investigation in the treatment of both hypoleptinemia and hyperleptinemia-related syndrome. Initially studied to reverse obesity, leptin replacement has only reversed obesity in leptin-deficient conditions, with replacement in typically obese individuals with elevated leptin levels showing limited efficacy. It has FDA approval for the treatment of congenital or acquired generalized lipodystrophy (non-HIV-related). Particular studies show leptin replacement has efficacy in reversing some abnormalities present in the above-mentioned syndromes, but these conditions are not yet a recognized indication for the use of recombinant leptin as a treatment.[12]