Partial leptin deficiency and human adiposity

Farooqi, I. Sadaf; Keogh, Julia M.; Kamath, S. K.; Jones, Sarah; Gibson, William T.; Trussell, Rebecca; Jebb, Susan A.; Lip, Gregory Y. H.; O’Rahilly, Stephen

doi:10.1038/35102112

Cited by 364 publications

(235 citation statements)

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“…37 Alternatively, a genetically determined decrease in production of IL-6 per weight adipose tissue might theoretically cause increased obesity and thereby partly conceal the decrease in IL-6 levels in the blood circulation, in a similar way as reported for partial leptin Interleukin-6 promoter polymorphism and overweight I Wernstedt et al deficiency. 38 This possibility is supported by the findings that serum IL-6/leptin ratios, used as a surrogate marker for IL-6 production per adipose tissue mass, were found to be decreased in À174 C allele-containing genotypes. The comparatively high serum IL-6 levels in obese individuals could implicate IL-6 resistance in a similar way as they are assumed to be leptin resistant.…”

Section: Discussionsupporting

confidence: 69%

A common polymorphism in the interleukin-6 gene promoter is associated with overweight

et al. 2004

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OBJECTIVE:Human body fat mass is to a large extent genetically determined, but little is known about the susceptibility genes for common obesity. Interleukin-6 (IL-6) suppresses body fat mass in rodents, and IL-6 treatment increases energy expenditure in both rodents and humans. The À174 G/C single-nucleotide polymorphism (SNP) in the IL-6 gene promoter is common in many populations, and À174 C-containing promoters have been found to be weaker enhancers of transcription. Moreover, a SNP at position À572 in the IL-6 promoter has recently been reported to affect transcription. The objective was to investigate the association between the IL-6 gene promoter SNPs and obesity. DESIGN: Trans-sectional association study of IL-6 gene promoter SNPs and indices of obesity. SUBJECTS: Two study populations, the larger one consisting of hypertensive individuals (mean age 57 y, 73% males, n ¼ 485) and the other consisting of 20 y younger nonobese healthy females (n ¼ 74). MEASUREMENTS: Genotyping for the À174 IL-6 G/C and the À572 G/C SNPs, body mass index (BMI), serum leptin levels, serum IL-6 levels, C-reactive protein, fasting blood glucose and various blood lipids. RESULTS: The common À174 C allele (f C ¼ 0.46), but not any À572 allele, was associated with higher BMI and higher serum leptin levels in both study populations. In the larger population, there were significant odds ratios for the association of CC (2.13) and GC (1.76) genotypes with overweight (BMI425 kg/m 2 ). Moreover, as the C allele was common, it accounted for a significant population-attributable risk of overweight (12%; CI 2-21%), although its average effect was modest in this sample. CONCLUSION: Genetically determined individual differences in production of IL-6 may be relevant for the regulation of body fat mass.

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Section: Discussionsupporting

confidence: 69%

A common polymorphism in the interleukin-6 gene promoter is associated with overweight

et al. 2004

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“…Leptin, the product of the ob gene, plays a central role in the regulation of food intake and energy expenditure (4). Mutations in the leptin pathway can be a cause of human obesity (5)(6)(7). In children with complete leptin deficiency and who are still in the process of gaining weight and developing obesity, leptin replacement therapy can lead to substantial weight reduction (8,9).…”

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confidence: 99%

Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults

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et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

446

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Genetic mutations in the leptin pathway can be a cause of human obesity. It is still unknown whether leptin can be effective in the treatment of fully established morbid obesity and its endocrine and metabolic consequences in adults. To test the hypothesis that leptin has a key role in metabolic and endocrine regulation in adults, we examined the effects of human leptin replacement in the only three adults identified to date who have genetically based leptin deficiency. We treated these three morbidly obese homozygous leptin-deficient adult patients with recombinant human leptin at low, physiological replacement doses in the range of 0.01-0.04 mg͞kg for 18 months. Patients were hypogonadal, and one of them also had type 2 diabetes mellitus. We chose the doses of recombinant methionyl human leptin that would achieve normal leptin concentrations and administered them daily in the evening to model the normal circadian variation in endogenous leptin. The mean body mass index dropped from 51.2 ؎ 2.5 (mean ؎ SEM) at baseline to 26.9 ؎ 2.1 kg͞m 2 after 18 months of treatment, mainly because of loss of fat mass. We document here that leptin replacement therapy in leptin-deficient adults with established morbid obesity results in profound weight loss, increased physical activity, changes in endocrine function and metabolism, including resolution of type 2 diabetes mellitus and hypogonadism, and beneficial effects on ingestive and noningestive behavior. These results highlight the role of the leptin pathway in adults with key effects on the regulation of body weight, gonadal function, and behavior.T he increasing rates of obesity and consequent morbidity represent a major epidemic worldwide and threaten to bankrupt health care systems (1-3). While prevention is of great importance, it is medically relevant to identify biological pathways with the potential to treat obesity and related disorders, particularly in adults with fully established obesity and comorbid conditions, such as type 2 diabetes mellitus. Leptin, the product of the ob gene, plays a central role in the regulation of food intake and energy expenditure (4). Mutations in the leptin pathway can be a cause of human obesity (5-7). In children with complete leptin deficiency and who are still in the process of gaining weight and developing obesity, leptin replacement therapy can lead to substantial weight reduction (8,9).It is still unknown whether the leptin pathway is relevant to the treatment of established morbid obesity and its endocrine and metabolic consequences in adults. We addressed this question by treating three homozygous leptin-deficient adults with morbid obesity. Morbid obesity had been fully established for two to four decades in those patients, and they had been at a stable (but very high) weight for Ͼ10 years. They were hypogonadal, and one of them had type 2 diabetes mellitus. We report here the results of the first 18 months of replacement therapy with recombinant human leptin, showing that leptin is highly effective in dramatically reducing...

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“…Its existence was hypothesized by Coleman et al (1969;1973) in studying two mutant mouse strains, namely the ob/ob and db/db mice which have a phenotype of massive overeating, obesity and delay of sexual maturation. Further, this peptide hormone was cloned and demonstrated to be mainly synthesized by adipose cells (Zhang et al, 1994), in proportion to the adipose-cell mass (Maffei et al, 1995) although a recent study reports a partial leptindeficiency in patients having an increased body fat mass (Farooqi et al, 2001). Leptin release occurs in response to a food intake signal to act both peripherally and in the brain (Auwerx and Staels, 1998).…”

Section: Ii1b : How Do Brain Genes "Integrate the Food Signals"?mentioning

confidence: 99%

Genes involved in obesity: Adipocytes, brain and microflora

et al. 2006

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Obesity and obesity-related disorders such as cardiovascular diseases and metabolic abnormalities including hypertension, hyperinsulinemia, insulin-resistance and type 2 diabetes, are among the most pressing problems in the industrialized world (Friedman, 2003;Kannel et al., 1991 (Reitman et al., 2000), demonstrating that normal adipose tissue development and function is critical for metabolic homeostasis.Obesity results from complex interactions between genes and environmental factors such as diet, food components and/or way of life, and can be viewed as an energy storage disorder in which weight gain results from an energy imbalance (i.e. energy input exceeding output), with most of the excess calories stored as triglycerides in adipose tissue (Smith et al., 2006). Therefore a great deal of attention has focused on the mechanisms controlling food intake and adipose mass, and is of considerable importance for public health and clinical medicine.In this review, we prevalently highlight the complex relationships existing between the white adipose tissue, the central nervous system, the endogenous microbiota, and nutrition. Throughout, we emphasize the most recent findings in the field and consider how it shapes the past knowledge and forecasts the future of research on metabolic disorders, such as obesity.

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Partial leptin deficiency and human adiposity

Cited by 364 publications

References 8 publications

A common polymorphism in the interleukin-6 gene promoter is associated with overweight

A common polymorphism in the interleukin-6 gene promoter is associated with overweight

Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults

Genes involved in obesity: Adipocytes, brain and microflora

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