Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency

Farooqi, I. Sadaf; Matarese, Giuseppe; Lord, Graham; Keogh, Julia M.; Lawrence, Elizabeth; Agwu, Juliana Chizo; Sanna, Veronica; Jebb, Susan; Perna, Francesco; Fontana, Silvia; Lechler, Robert I.; DePaoli, Alex M.; O’Rahilly, Stephen

doi:10.1172/jci0215693

Cited by 1,148 publications

(777 citation statements)

References 41 publications

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“…Strikingly, we have shown that the principal impact of leptin on these children is a marked reduction in spontaneous food intake. 30,31 Thus, we were able to complete the 'Koch's postulates' for leptin as an appetite regulatory hormone in humans and confirmed that human appetite and food intake, similar to the mouse, are dependent on the presence of an active leptin signaling pathway. In subsequent years, we and others have shown that human obesity can result from a multiplicity of defects in the downstream pathways of leptin signaling within the brain.…”

Section: Discussionsupporting

confidence: 59%

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: Discussionsupporting

confidence: 59%

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 studies of the effects of leptin administration on TSH, findings differed depending on whether basal TSH concentrations or TSH secretion were examined. For example, administration of leptin to leptindeficient children 47 and healthy adults 48 increases thyroid hormones without altering basal TSH concentration. In contrast, leptin replacement significantly blunts the 24-hour TSH (µU/ml) 24-hour leptin (ng/ml) Figure 3 Linear relationship between mean 24-h levels of leptin and TSH in 16 morbidly obese subjects basally (open circles), in 7 morbidly obese subjects after 6 months of surgery (filled circles) and in lean control subjects (filled triangles).…”

Section: Discussionmentioning

confidence: 99%

Daylong pituitary hormones in morbid obesity: effects of bariatric surgery

et al. 2008

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Moderate obesity is known to be associated with multiple endocrine abnormalities. Less information is available on the hormonal status of patients with morbid obesity and on the effects of major weight loss. We studied 16 severely obese (BMI 40.6-69.9 kg/m 2 ) nondiabetic patients and 7 nonobese (BMI range 24.6-27.7 kg/m 2 ), sex-and age-matched healthy volunteers. During 24 h in a metabolic ward, four meals were administered and hourly blood samples were drawn from a central venous catheter for the measurement of glucose, insulin, leptin, thyrotropic hormone (TSH), growth hormone (GH) and prolactin. Insulin sensitivity was measured by a euglycaemic hyperinsulinaemic clamp. Studies were repeated 6 months after biliopancreatic diversion, a mainly malabsorptive surgical approach, which caused an average weight loss of 35±4 kg (or 26 ± 2% of initial weight). Compared with controls, patients were hyperinsulinaemic (290 ± 31 vs 88 ± 4 pmol l À1 , P ¼ 0.0002), insulin resistant (23.5±2.8 vs 52.9±4.9 mmol min À1 kg FFM À1 , P ¼ 0.0006) and hyperleptinaemic (52.5±5.8 vs 10.9±3 ng ml À1 , P ¼ 0.0002). Plasma TSH levels were increased throughout the day-night cycle (averaging 2.02 ± 0.18 vs 1.09 ± 0.19 mU ml À1 of controls, P ¼ 0.01), whereas serum GH levels were suppressed (0.46±0.10 vs 3.01±1.15, P ¼ 0.002). Following surgery, the hyperinsulinaemia and insulin resistance were fully normalized; in concomitance with a major drop in leptin levels (to 14.4±2.7 ng ml À1 , P ¼ 0.02), TSH decreased and GH increased to near-normal levels. In the whole dataset, mean 24-h leptin levels were directly related to mean 24-h TSH levels after controlling for confounders this relationship was lost only after adjusting for fat mass. We conclude that in morbid obesity leptin is a determinant of changes in pituitary function.

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“…55,92 FUTURE PROSPECTS Exogenous leptin administration in children with a congenital leptin deficiency normalized the absolute numbers of Tregs, enhanced CD4 1 counts, restored proliferative responses, and promoted the cytokine release profile from lymphocytes. 15 Furthermore, it has been demonstrated that the exogenous administration of recombinant methionyl human leptin in subjects with acquired leptin deficiency improves their circulating cytokine levels. 44 However, there is a huge amount of data on the promotion of inflammation by high circulating leptin levels.…”

Section: Leptin Connective Tissue Diseases and Organ-specific Autoimmentioning

confidence: 99%

Leptin in immuno-rheumatological diseases

et al. 2011

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Leptin is one of the most important hormones secreted by adipocytes, with a variety of physiological roles related to the control of metabolism and energy homeostasis. Since its discovery in 1994, leptin has attracted increasing interest in the scientific community for its pleiotropic actions. One of these functions is the relationship between nutritional status and immune competence. It structurally resembles proinflammatory cytokines, such as IL-6 and IL-12. The cytokine-like structural characteristic of leptin is implicative of its function in regulating immune responses. The role of leptin in regulating immune responses has been assessed in vitro as well as in clinical studies. It has been shown that disease conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders, such as autoimmune diseases, are associated with the increased secretion of leptin and the production of proinflammatory pathogenic cytokines. In this paper, we review the most recent advances of the role of leptin in immune-rheumatological diseases, and we discuss whether strategies aimed at modifying leptin levels could represent innovative and therapeutic tools for autoimmune disorders. Keywords: adipokines; autoimmune diseases; leptin; rheumatic diseases INTRODUCTIONThe existence of a factor secreted by white adipose tissue (WAT), which acts to control feeding, weight and WAT mass, was first proposed by Kennedy 1 and is supported by monogenic mutations resulting in obesity. [2][3][4] WAT is composed of adipocytes filled mainly with triacylglycerol and embedded in loose connective tissue containing adipocyte precursors, fibroblasts, immune and other cells. Obesity, the condition that originally motivated the research on WAT, is characterized by low-grade systemic inflammation. It is thought that excess WAT can contribute to the maintenance of obesity through inflammation-inducing lipotoxicity by secreting factors that stimulate the synthesis of inflammatory agents in other organs and by secreting inflammatory agents itself. 5 The current view of WAT states that it is an active contributor to body homeostasis by sending out and responding to signals that modulate appetite, energy expenditure, insulin sensitivity, the endocrine and reproductive systems, bone metabolism, inflammation and immunity. 6 Several findings have converged to indicate that adipocytes share certain properties with immune cells, such as complement activation 7 and proinflammatory cytokine production. 8 Fat cell precursors also share features with macrophages. Numerous genes that code for transcription factors, cytokines, inflammatory signaling molecules, and fatty acid transporters are essential for adipocyte biology and are also expressed and functional in macrophages. 9 Adipose tissue secrets a variety of factors: the term 'adipokine' is generally given to any protein that can be synthesized and secreted by adipocytes. Among these factors, only leptin and adiponectin (and possibly resistin, adipsi...

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Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency

Cited by 1,148 publications

References 41 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

Daylong pituitary hormones in morbid obesity: effects of bariatric surgery

Leptin in immuno-rheumatological diseases

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