Congenital leptin deficiency is associated with severe early-onset obesity in humans

Montague, Carl; Farooqi, I. Sadaf; Whitehead, Jonathan P.; Soos, Maria A.; Rau, Harald; Wareham, Nicholas J.; Sewter, Ciaran; Digby, Janet E.; Mohammed, Shehla; Hurst, Jane A.; Cheetham, C H; Earley, A R; Barnett, Anthony; Prins, Johannes B.; O’Rahilly, Stephen

doi:10.1038/43185

Cited by 2,646 publications

(1,623 citation statements)

References 19 publications

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“…We found that leptin levels were undetectable, and that these children were homozygous for a frameshift/premature stop mutation in the leptin gene that prevented all normal leptin production. 29 It is a rare privilege in medical research to identify a new condition that is so obviously amenable to treatment. In these and in seven subsequent children with severe obesity associated with complete leptin deficiency, we have been able (with the support of amgen and subsequently amylin) to administer daily injections with recombinant leptin with remarkably beneficial effects on body weight.…”

Section: Discussionmentioning

confidence: 99%

Human obesity as a heritable disorder of the central control of energy balance

O’Rahilly

Farooqi

2008

Int J Obes

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In the spirit of celebration associated with the 20th anniversary of the Pennington Biomedical Research Center, we have seized the opportunity of taking a highly personal and not at all comprehensive 'whistle-stop tour' of a large body of evidence that, we feel, supports the following conclusions: (1) that body fat stores are regulated by biological control processes in humans as they are in lower animals; (2) that there are major inherited influences on the efficiency whereby such control processes operate in humans; (3) that the precise nature of those genetic and biological influences and how they interact with environmental factors are beginning to be understood; (4) that most of the genes discovered thus far have their principal impact on hunger, satiety and food intake; (5) that while there is understandable resistance to the notion that genes can influence a human behavior such as the habitual ingestion of food, the implications of these discoveries are essentially benign. Indeed, we hope that they may eventually lead to improved treatment for patients and, in addition, help to inculcate a more enlightened attitude to the obese with a reduction in their experience of social and economic discrimination.

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Section: Discussionmentioning

confidence: 99%

Human obesity as a heritable disorder of the central control of energy balance

O’Rahilly

Farooqi

2008

Int J Obes

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“…13 The disabling obesity of leptin deficiency is characterized by the selective deposition of fat and children often develop valgus deformities of the knees by the age of 5-6 y, sleep apnoea and high rates of childhood infection and atopic disease due to abnormalities of T-cell number and function. 14 Hypothalamic hypothyroidism is seen at a young age with a subsequent failure to undergo pubertal development due to hypogonadotropic hypogonadism.…”

Section: Congenital Leptin and Leptin Receptor Deficiencymentioning

confidence: 99%

New advances in the genetics of early onset obesity

Farooqi

O’Rahilly

2005

Int J Obes

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“…1 Also in humans some cases of extreme obesity are known, which are caused by leptin deficiency, as a result of rare mutations in the leptin gene. 2 Injecting these humans or ob/ob mice with leptin reduces their food intake and brings them back to lower body weight. [3][4][5] Serum leptin concentrations are positively correlated with the amount of fat mass in the body.…”

Section: Introductionmentioning

confidence: 99%

Fasting leptin and appetite responses induced by a 4-day 65%-energy-restricted diet

et al. 2005

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Objective: Animal studies show that the leptin decline after acute severe caloric restriction is a peripheral signal to increase food intake. However, most human studies have failed to observe such a relationship. We studied the acute effects of severe caloric restriction on the association between serum leptin concentrations and subjective appetite. Subjects: A total of 44 healthy adult men (aged: 4375 years; BMI: 27.373.2 kg/m 2 ). Measurements: Fasting serum leptin concentrations and self-perceived appetite levels were measured during a 4-day diet containing 36% of the estimated energy requirements. Appetite levels were assessed with a 10-point Likert scale, reflecting hunger, fullness, desire to eat, prospective consumption and total appetite. Results: After the 4-day energy deficit, fasting leptin concentrations decreased by 39.4% (95% CI: À43.6; À34.9%). This decline was associated with an increase in fasting hunger (r ¼ À0.42; Po0.01), desire to eat (r ¼ À0.39; Po0.05) and total appetite (r ¼ À0.38; Po0.05). Furthermore, the association between fasting leptin concentrations and fasting appetite levels became stronger during the energy restriction period (for total appetite: day 0 r ¼ À0.15, P ¼ 0.32; day 2 r ¼ À0.31, P ¼ o0.05; day 4 r ¼ À0.41, Po0.01). Conclusions: The acute proportional reduction in fasting leptin after 4-day energy restriction is associated with an increase in self-perceived appetite. Additionally, the inverse association between proportional fasting leptin concentrations and selfperceived appetite response becomes stronger as energy restriction is prolonged. These findings suggest that leptin has an instrumental role in restoring energy balance in humans through the expression of appetite.

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Congenital leptin deficiency is associated with severe early-onset obesity in humans

Cited by 2,646 publications

References 19 publications

Human obesity as a heritable disorder of the central control of energy balance

Human obesity as a heritable disorder of the central control of energy balance

New advances in the genetics of early onset obesity

Fasting leptin and appetite responses induced by a 4-day 65%-energy-restricted diet

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