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Leptin and Human Obesity

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The search for mutations of the Leptin gene in humans revealed that most obese humans had normal Leptin genes. Diabetes. 1996 May;45(5):679-82 World over, only a handful of families with homozygous mutation in the Leptin gene have been identified with congenital Leptin deficiency, characterised in all cases by severe early onset obesity, high fat mass, and impaired satiety with marked hyperphagia  Nature. 1997 Jun 26;387(6636):903-8;   Nat Genet. 1998 Mar;18(3):213-5;  J Clin Endocrinol Metab. 1999 Oct;84(10):3686-95   Heterozygous mutation of the Leptin gene- identified in family members of affected homozygous patients-was not associated with morbid obesity or Leptin deficiency. Leptin treatment of these homozygous patients with Leptin deficiency corrects the obesity and hyperphagia. J Clin Invest. 2002 Oct;110(8):1093-103;  N Engl J Med. 1999 Sep 16;341(12):879-84  although development of antibodies to Leptin in these patients resulting in tolerance to Leptin effects remain a concern.  Eur J Endocrinol. 2002 Oct;147(4):435-41.   Note that in contrast to the animal model of ob gene absence, humans without the Leptin gene  are not diabetic.  Patients with lipodystrophy have little or no fat mass and hence have little or no Leptin. As there is no fat tissue for the triglycerides to be deposited in, ectopic deposition of triglycerides occurs in muscles and liver with insulin resistance. Leptin treatment of these patients improves their hypertriglyceridaemia and insulin resistance. 

Leptin and COMMON OBESITY
Leptin deficient ob/ob mice responded to Leptin injections with reduction of food intake and concomitant weight loss. Normal mice also demonstrated similar responses to a lesser degree. Science. 1995 Jul 28;269(5223):540-3  Diet-induced obese mouse demonstrate reduction in food intake and weight loss only at higher Leptin doses than ob/ob mice suggesting a degree of Leptin resistance. Science. 1995 Jul 28;269(5223):546-9  In humans, Leptin is produced predominantly in white adipose tissue. Diabetes. 1995 Jul;44(7):855-8  Fasting decreases and eating increases Leptin levels N Engl J Med. 1996 Feb 1;334(5):292-5  both in the short term and long term,  J Clin Endocrinol Metab. 1996 Nov;81(11):4162-5  suggesting that the main role of Leptin is to regulate energy metabolism by signaling to the hypothalamus producing a reduction in food intake. One would have simplistically assumed that a deficiency in Leptin would be responsible for human obesity! Interestingly, serum levels of Leptin are directly proportional to fat massand BMI such that obese humans have higher amounts of plasma Leptin. N Engl J Med. 1996 Feb 1;334(5):292-5. Most obese humans have, on average,  Leptin levels 4 times higher than non-obese individuals suggesting Leptin resistance rather than deficiency! Not surprisingly, the ob gene was over-expressed in the adipose tissue of obese humans.Nat Med. 1995 Sep;1(9):950-3  
Leptin receptors have been identified in the hypothalamus. Leptin receptor defects could potentially account for the Leptin resistance or Leptin insensitivity seen in the obese. Although such receptor defects have been described in rat models (db/db mouse model and fatty fa/fa rats) they have not been described in humans. Diabetes. 1996 Jul;45(7):992-4;  Obes Res. 1998 Mar;6(2):122-7   A single case of Leptin receptor gene mutation has been described resulting in obesity, absent pubertal development, and impaired growth hormone and TSH secretion with Leptin levels as high as 700 ng/ml in the homozygotes.  Nature. 1998 Mar 26;392(6674):398-401  Leptin receptor polymorphisms seem more likely to be implicated in common obesity, although none of the presently described polymorphisms are associated with major disturbances in fat mass. Diabetes. 1997 Nov;46(11):1898-900 ;   Int J Obes Relat Metab Disord. 2002 May;26(5):640-6 . Defective Post-receptor or intracellular signalling are also likely to be contributing factors. Pathways downstream of Leptin signalling might also be defective resulting in impaired Leptin action as seems to be the case in Agouti mice (Ay/a),   Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8878-83.  Leptin actions may be mediated partly through the melanocortin4 receptor pathways which is interfered with, by the Melanocortin antagonist-Agouti in these mice. Intracellular molecules as Suppressors of the cytokine signalling family (SOCS-3) have also been shown to potently inhibit Leptin signalling. Front Neuroendocrinol. 2000 Jul;21(3):263-307.
The possibility that the increased Leptin in obese patients was an inactive form was considered. Studies have distinguished the free and bound forms of the Leptin, demonstrating that the obese have a higher proportion of the free (bioactive) Leptin J Clin Invest. 1996 Sep 15;98(6):1277-82  in keeping with the Leptin resistance hypothesis.   Most of the Leptin in the lean was the bound form, which might make it unable to cross the blood brain barrier, and thus preventing satiety induction in those with low fat mass. Leptin is a large protein and the large fenestrated capillaries of the median eminence may make it possible for Leptin to diffuse into the CNS to exert its actions on the ventrobasal hypothalamus, Endocrinology. 1997 Feb;138(2):839-42   including the ventromedial, dorsomedial, and ventral premammillary hypothalamic nuclei.
An impaired trans-BBB transport of Leptin has been described in the New Zealand obese mouse which is unresponsive to peripherally administered Leptin but responsive to intra-cerebroventricular Leptin administration. J Clin Invest. 1997 Feb 1;99(3):385-90. Similar factors might be involved in obese humans. LRa, the short form of the Leptin receptor, is a protein expressed in the choroid plexus, which facilitates the transport of Leptin into the CSF.  Nature. 1996 Feb 15;379(6566):632-5.  This transporter system is saturable. Leptin levels in CSF has been shown to be lower than plasma Leptin levels in obese humans, suggesting decreased Leptin signalling in the brain despite high serum levels. Nat Med. 1996 May;2(5):589-93  Hypothalamic interstitial Leptin levels may also be low in keeping with the lower CSF Leptin levels. Despite this, CSF Leptin levels, like serum Leptin levels,  correlate with BMI.  High doses of peripheral Leptin administration can overcome the saturable Leptin transport system and produce higher CSF Leptin levels.  JAMA. 1999 Oct 27;282(16):1517-8    However there seems to be a threshold plasma Leptin concentration (about 25 ng/ml) above which the transport of Leptin into the CSF does not increase further despite large increases in plasma Leptin levels. Hence the hyper-Leptinaemia of obese patients is probably not translated into hypothalamic signalling. Ann N Y Acad Sci. 2002 Jun;967:379-88.  Yet, the brain contributes to a substantial amount of the plasma Leptin pool, with greater contributions in the obese compared to the lean. Am J Physiol Endocrinol Metab. 2004 May;286(5):E744-52  It has been suggested that triglycerides may impair the transport of Leptin into the CSF.Diabetes. 2004 May;53(5):1253-60.
Large fat cells express more ob mRNA than small fat cells. Nat Med. 1995 Sep;1(9):953-6.   Obese patients have more of large fat cells due to hypertrophy and hyperplasia. A threshold size or cell stretching exists for the fat cells filling with lipid for the expression of the ob gene and thus Leptin production. Annu Rev Nutr. 1992;12:207-33.   Subcutaneous fat releases more Leptin than visceral adipose tissue partly accounting for the unfriendly nature of the latter,  Endocrinology. 2004 May;145(5):2273-82 and the higher levels of Leptin in women. Insulin stimulates and catecholamines suppress Leptin release by adipose tissue.