Introduction
Leptin is a peptide hormone released from adipose tissue and encoded by the obese (ob) gene. While leptin's role is classically described in the regulation of appetite, neuroendocrine function, and energy homeostasis, it seems to influence several other physiological processes. These include metabolism, endocrine regulation, and immune function, with possible other functions still awaiting characterization. Leptin abnormalities have associations with a variety of metabolic syndromes, particularly obesity. The study of leptin physiology has contributed to our understanding of energy homeostasis, and it seems likely that it plays a pivotal role in developing effective treatments for the growing obesity epidemic. Total body fat mass index (BMI), metabolic hormones, and gender are the factors that most strongly influence circulating plasma leptin concentrations. Women have higher levels of circulating leptin compared to men.[1]
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 comprises 146 amino acids and is produced through mRNA-directed protein synthesis.[3] Its structure is similar to that of 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 effects by binding to leptin receptors on cell surfaces. Leptin receptors are present on neuronal, hepatic, pancreatic, cardiac, and intestinal tissue.
Mechanism
The leptin receptor belongs to the glycoprotein 130 family of cytokine receptors and comprises 6 isoforms. 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 leptin receptor is the JAK-STAT pathway. As leptin binds, it dimerizes the leptin receptor. This dimerization leads to JAK2 tyrosine kinase phosphorylating 3 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. STAT3 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, and growth hormone axes, as well as 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, resulting in a 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 signaling, which signals an energy deficit and triggers a cascade of responses to help the body cope 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 hormone levels, and reproductive hormone levels, as well as reduced energy expenditure and growth. As this signal, leptin is the catalyst for the body's transition into a starvation mode, a global adaptation 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 adipose tissue accumulates, there is a concurrent rise in leptin production and secretion into the bloodstream. With increased leptin comes inhibition of the body’s starvation mode, thereby reducing food intake and increasing energy expenditure to counteract the current energy surplus.
Clinical Significance
Leptin deficiency or resistance is associated with dysregulated cytokine production, increased susceptibility to infections, autoimmune disorders, malnutrition, and heightened inflammatory responses.
Pathophysiology and Clinical Relevance
Hypoleptinemia
Complete leptin deficiency results in the clinical phenotypes of severe obesity, impaired satiety, intense 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 plays in the body, many of which are not well understood and remain under active investigation. Congenital forms of hypoleptinemia result from mutations in the LEP or leptin receptor genes 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 leptin's anorectic and body-weight-reducing effects. 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, with obese individuals having higher serum leptin levels and adipocyte LEP mRNA content than normal-weight individuals. Also, serum leptin levels and adipocyte LEP mRNA content decrease with weight reduction. The mechanism of resistance appears to be related to defects in leptin transport across the blood-brain barrier or in intracellular signaling downstream of the leptin receptor. 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). Specific studies show that leptin replacement is effective in reversing some abnormalities in the above-mentioned syndromes, but these conditions are not yet recognized indications for the use of recombinant leptin as a treatment.[12]
References
- 1.
Grinspoon S, Gulick T, Askari H, Landt M, Lee K, Anderson E, Ma Z, Vignati L, Bowsher R, Herzog D, Klibanski A. Serum leptin levels in women with anorexia nervosa.
J Clin Endocrinol Metab. 1996 Nov;81(11):3861-3. [
PubMed: 8923829]
- 2.
Gong DW, Bi S, Pratley RE, Weintraub BD. Genomic structure and promoter analysis of the human obese gene.
J Biol Chem. 1996 Feb 23;271(8):3971-4. [
PubMed: 8626726]
- 3.
Wasim M, Awan FR, Najam SS, Khan AR, Khan HN. Role of Leptin Deficiency, Inefficiency, and Leptin Receptors in Obesity.
Biochem Genet. 2016 Oct;54(5):565-72. [
PubMed: 27313173]
- 4.
Peelman F, Zabeau L, Moharana K, Savvides SN, Tavernier J. 20 years of leptin: insights into signaling assemblies of the leptin receptor.
J Endocrinol. 2014 Oct;223(1):T9-23. [
PubMed: 25063754]
- 5.
Allison MB, Myers MG. 20 years of leptin: connecting leptin signaling to biological function.
J Endocrinol. 2014 Oct;223(1):T25-35. [
PMC free article: PMC4170570] [
PubMed: 25232147]
- 6.
Amjad S, Baig M, Zahid N, Tariq S, Rehman R. Association between leptin, obesity, hormonal interplay and male infertility.
Andrologia. 2019 Feb;51(1):e13147. [
PubMed: 30255520]
- 7.
Farr OM, Gavrieli A, Mantzoros CS. Leptin applications in 2015: what have we learned about leptin and obesity?
Curr Opin Endocrinol Diabetes Obes. 2015 Oct;22(5):353-9. [
PMC free article: PMC4610373] [
PubMed: 26313897]
- 8.
Flier JS, Maratos-Flier E. Leptin's Physiologic Role: Does the Emperor of Energy Balance Have No Clothes?
Cell Metab. 2017 Jul 05;26(1):24-26. [
PubMed: 28648981]
- 9.
Funcke JB, von Schnurbein J, Lennerz B, Lahr G, Debatin KM, Fischer-Posovszky P, Wabitsch M. Monogenic forms of childhood obesity due to mutations in the leptin gene.
Mol Cell Pediatr. 2014 Dec;1(1):3. [
PMC free article: PMC4644131] [
PubMed: 26567097]
- 10.
Farooqi IS, O'Rahilly S. 20 years of leptin: human disorders of leptin action.
J Endocrinol. 2014 Oct;223(1):T63-70. [
PubMed: 25232148]
- 11.
Peters T, Antel J, Föcker M, Esber S, Hinney A, Schéle E, Dickson SL, Albayrak Ö, Hebebrand J. The association of serum leptin levels with food addiction is moderated by weight status in adolescent psychiatric inpatients.
Eur Eat Disord Rev. 2018 Nov;26(6):618-628. [
PubMed: 30252189]
- 12.
Paz-Filho G, Mastronardi CA, Licinio J. Leptin treatment: facts and expectations.
Metabolism. 2015 Jan;64(1):146-56. [
PubMed: 25156686]
Disclosure: Sean Dornbush declares no relevant financial relationships with ineligible companies.
Disclosure: Narothama Aeddula declares no relevant financial relationships with ineligible companies.
