Congenital Leptin Deficiency Mechanism

Most patients with congenital leptin deficiency tend to be conceived in primarily consanguineous relationships(1). The underlying cause is a genetic mutation in the leptin receptor (LEPR) gene, which results in a defective protein being translated and transcribed(2).  Leptin acts on the anorexigenic pathway to promote satiety. A deficiency in this regulatory protein results in an unchecked appetite and early onset obesity.

Effects of leptin on fertility and thyroid function?

  1. Hypothalamic-pituitary-thyroidal axis: Leptin regulates the release of thyroid-stimulating hormone (TSH)(3). Patients with this condition are prone to developing central hypothyroidism due to leptin-mediated signaling defects in the hypothalamic-pituitary-thyroid axis. To further substantiate the role of leptin in the HPT axis, exogenous leptin replacement dramatically results in the amelioration of hypothyroidism (4).
  1. Hypogonadotropic-pituitary-gonadal axis: Also, leptin regulates the pulsatile release of gonadotropin-releasing hormone (GnRH)(5). In effect, aatients with congenital leptin deficiency develop central hypogonadism due to defective GnRH synthesis and release(3).

Mechanism of Obesity in Congenital Leptin Deficiency

Congenital leptin deficiency classically pesents with early-onset obesity(6), due to patients exhibiting food-seeking behavior(2).

 Pathophysiology

  1. Progressive deposition of fat mass, mainly white adipose tissue due to excess caloric intake is the primary cause of obesity(7). Leptin, is a hormone produced by white adipose tissue, which is involved in triggering satiety through the central anorexigenic pathway(6). Mechanistically, leptin binds to its cognate leptin receptors present on pro-opiomelanocortin (POMC) processing neurons situated in the arcuate nucleus of the hypothalamus to cause satiety(8). Consequently, patients with congenital leptin deficiency present with an unchecked appetite (hyperphagia), promoting excess weight gain (6).
  1. Furthermore, leptin increases energy expenditure by augementing sympathetic nerve impulses in brown adipose tissue, thereby increasing thermogenesis. Blunting of this sympathetic effect in brown adipose tissue occurs in leptin deficiency thus reduced energy expenditure and promoting obesity(5).
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References

  1. Saeed S, Arslan M, Froguel P. Genetics of Obesity in Consanguineous Populations: Toward Precision Medicine and the Discovery of Novel Obesity Genes. Obesity. 2018;26(3):474–84.
  2. Wabitsch M, Funcke JB, Lennerz B, Kuhnle-Krahl U, Lahr G, Debatin KM, et al. Biologically inactive leptin and early-onset extreme obesity. N Engl J Med. 2015 Jan 1;372(1):48–54.
  3. Paz-Filho G, Mastronardi CA, Licinio J. Leptin treatment: Facts and expectations. Metabolism. 2015 Jan 1;64(1):146–56.
  4. Paz-Filho G, Delibasi T, Erol HK, Wong ML, Licinio J. Congenital leptin deficiency and thyroid function. Thyroid Res. 2009 Nov 4;2:11.
  5. Kelesidis T, Kelesidis I, Chou S, Mantzoros CS. Narrative Review: The Role of Leptin in Human Physiology: Emerging Clinical Applications. Ann Intern Med. 2010 Jan 19;152(2):93–100.
  6. 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.
  7. Paz-Filho G, Mastronardi C, Delibasi T, Wong ML, Licinio J. Congenital leptin deficiency: diagnosis and effects of leptin replacement therapy. Arq Bras Endocrinol Metabol. 2010 Nov;54(8):690–7.
  8. Dodd G, Descherf S, Loh K, Simonds SE, Wiede F, Balland E, et al. Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell. 2015 Jan 15;160(0):88–104.

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