Physiology, Leptin


Article Author:
Sean Dornbush


Article Editor:
Narothama Aeddula


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Andrew Wilt
Mary Cataletto


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Phillip Hynes
Tehmina Warsi


Updated:
1/4/2019 6:44:35 PM

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 will play a pivotal role in developing an effective treatment and a solution to the growing obesity epidemic. The total body fat mass index (BMI), metabolic hormones, and gender are the factors that have the greatest effect on circulating plasma leptin concentrations. Women have higher levels of circulating leptin compared to men.[1]

Cellular

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 perivascular intestinal tissue.

Mechanism:

The LR belongs to 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 a variety of 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 are 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 bodies transition into a starvation mode, which is 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, which specifically is 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 the transport of leptin 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 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]


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Physiology, Leptin - Questions

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In which of the following problems is leptin implicated?



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A patient with non-HIV related generalized lipodystrophy receives recombinant leptin as a treatment for their condition. Which protein is expected to show increased activity inside the patient’s adipocytes?



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An 8-year-old male presents to your office for recurrent infections. Past medical history is significant for morbid obesity, history of jaundice, and recurrent bacterial infections. The patient experienced a normal birth. The mother reports the child had rapid onset obesity soon after developing a ferocious appetite. She states she often finds the child in the pantry eating with the lights off and the door closed so no one else knows he is in there. She has also found stashes of food hidden away in his room. The physical exam is normal. Further workup shows a hormone deficiency. On which of these sites does the deficient hormone normally have an inhibitory effect?



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A 9-year-old female presents for jaundice. The mother states the child’s skin turned yellow three days ago, and could not think of any inciting factor. Past medical history is significant for morbid obesity and recurrent bacterial infections. The patient experienced a normal birth. The mother reports the child has a ferocious appetite. She also states she often finds the child eating in secret and has found stashes of food hidden throughout the house. The patient has had no previous surgeries and is on no medications. Vital signs are temperature 97.9 F, heart rate 79/minute, blood pressure 121/84 mmHg, respiratory rate of 19/minute, oxygen saturation of 99% on room air. The physical exam shows a purple blackening of the neck and axillary folds and morbid obesity. Significant labs are a fasting insulin level of 49 mIU/L and serum LDL-C of 199 mg/dl. Which medical issue is the patient most likely to deal with later in life?



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What symptom is most associated with a deficiency in leptin?



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Physiology, Leptin - References

References

Association between leptin, obesity, hormonal interplay and male infertility., Amjad S,Baig M,Zahid N,Tariq S,Rehman R,, Andrologia, 2018 Sep 25     [PubMed]
The association of serum leptin levels with food addiction is moderated by weight status in adolescent psychiatric inpatients., Peters T,Antel J,Föcker M,Esber S,Hinney A,Schéle E,Dickson SL,Albayrak Ö,Hebebrand J,, European eating disorders review : the journal of the Eating Disorders Association, 2018 Sep 4     [PubMed]
Gong DW,Bi S,Pratley RE,Weintraub BD, Genomic structure and promoter analysis of the human obese gene. The Journal of biological chemistry. 1996 Feb 23     [PubMed]
Wasim M,Awan FR,Najam SS,Khan AR,Khan HN, Role of Leptin Deficiency, Inefficiency, and Leptin Receptors in Obesity. Biochemical genetics. 2016 Oct     [PubMed]
Peelman F,Zabeau L,Moharana K,Savvides SN,Tavernier J, 20 years of leptin: insights into signaling assemblies of the leptin receptor. The Journal of endocrinology. 2014 Oct     [PubMed]
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Farr OM,Gavrieli A,Mantzoros CS, Leptin applications in 2015: what have we learned about leptin and obesity? Current opinion in endocrinology, diabetes, and obesity. 2015 Oct     [PubMed]
Flier JS,Maratos-Flier E, Leptin's Physiologic Role: Does the Emperor of Energy Balance Have No Clothes? Cell metabolism. 2017 Jul 5     [PubMed]
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. Molecular and cellular pediatrics. 2014 Dec     [PubMed]
Farooqi IS,O'Rahilly S, 20 years of leptin: human disorders of leptin action. The Journal of endocrinology. 2014 Oct     [PubMed]
Paz-Filho G,Mastronardi CA,Licinio J, Leptin treatment: facts and expectations. Metabolism: clinical and experimental. 2015 Jan     [PubMed]
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. The Journal of clinical endocrinology and metabolism. 1996 Nov     [PubMed]

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