The role of melanocortin signalling in the control of body weight: evidence from human and murine genetic models

Yeo, Giles S.H.; Farooqi, I. Sadaf; Challis, Ben; Jackson, Robert S.; O’Rahilly, Stephen

doi:10.1093/qjmed/93.1.7

Cited by 105 publications

(52 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Of the five known melanocortin receptors, MC4R has been most-closely linked to control of energy balance in rodents (Yeo et al, 2000). Mice homozygous for a deleted MC4R become severely obese; heterozygotes have body weights intermediate between WT and homozygote null animals (Huszar et al, 1997).…”

Section: Human Mc4r Deficiencymentioning

confidence: 99%

“…In 1998, two groups reported heterozygous MC4R mutations in humans that were associated with dominantly inherited obesity (Vaisse et al, 1998;Yeo et al, 1998). Since then, heterozygous mutations in MC4R have been reported in obese humans from various ethnic groups (Hinney et al, 1999;Farooqi et al, 2000;Vaisse et al, 2000).…”

Section: Human Mc4r Deficiencymentioning

confidence: 99%

“…We identified a Ser66Thr mutation in heterozygous form in two unrelated U.K. probands. However, this did not co-segregate with obesity in family studies (Challis et al, 2000). In an Italian study, the Leu34Phe CART mutation was identified in the heterozygous state in a 10-year-old obese boy and a number of obese family members but no functional data were provided (del Giudice et al, 2001b).…”

Section: Other Possible Monogenic Syndromesmentioning

confidence: 99%

See 2 more Smart Citations

Monogenic Human Obesity Syndromes

Farooqi

O’Rahilly²

2004

Recent Progress in Hormone Research

115

View full text Add to dashboard Cite

Over the past decade, we have witnessed a major increase in the scale of scientific activity devoted to the study of energy balance and obesity. This explosion of interest has, to a large extent, been driven by the identification of genes responsible for murine obesity syndromes and the novel physiological pathways revealed by those genetic discoveries. We and others recently have identified several single-gene defects causing severe human obesity. Many of these defects have occurred in molecules identical or similar to those identified as a cause of obesity in rodents. This chapter will consider the human monogenic obesity syndromes that have been characterized to date and discuss how far such observations support the physiological role of these molecules in the regulation of human body weight and neuroendocrine function.

show abstract

Section: Human Mc4r Deficiencymentioning

confidence: 99%

Section: Human Mc4r Deficiencymentioning

confidence: 99%

Section: Other Possible Monogenic Syndromesmentioning

confidence: 99%

See 1 more Smart Citation

Monogenic Human Obesity Syndromes

Farooqi

O’Rahilly²

2004

Recent Progress in Hormone Research

115

View full text Add to dashboard Cite

show abstract

“…Intracellular posttranslational processing of the POMC propeptide by prohormone convertase 2 leads to the production in these neurons of ␣-, ␤-, and ␥-melanocyte-stimulating hormones. These peptides signal to downstream target neurons in the lateral hypothalamus that express the melanocortin receptors MC3R and MC4R with resultant decrease in food intake and increase in energy expenditure (5). Rare mutations in the POMC gene cause monogenic, severe, early-onset obesity in humans; however, the influence of common polymorphisms in POMC on obesity phenotypes in less extreme individuals is unclear (6).…”

mentioning

confidence: 99%

Association Between Common Polymorphisms of the Proopiomelanocortin Gene and Body Fat Distribution

et al. 2005

View full text Add to dashboard Cite

Rare mutations in the proopiomelanocortin (POMC) gene cause severe early-onset childhood obesity. However, it is unknown whether common variants in POMC are responsible for variation in body weight or fat distribution within the commonly observed range in the population. We tested for association between three polymorphisms spanning the POMC gene and obesity phenotypes in 1,428 members of 248 families. There was significant association between genotypes at the C8246T (P < 0.0001) and C1032G (P ‫؍‬ 0.003) polymorphisms and waist-to-hip ratio (WHR) corrected for age, sex, smoking, exercise, and alcohol consumption. Each T allele at C8246T (or G allele at C1032G) was associated with a 0.2-SD-higher WHR in a codominant fashion. When WHR was additionally corrected for BMI, thus providing a measure of body fat distribution throughout the range of BMI, there remained significant evidence for association with both markers that was of similar magnitude and statistical significance. There was no association between genotype at any polymorphism and BMI or plasma leptin level. These data show that genetic variants at the POMC locus influence body fat distribution within the normal range, suggesting a novel role for POMC in metabolic regulation. Diabetes 54: 2492-2496, 2005A bdominal obesity is a major risk factor for type 2 diabetes, coronary heart disease (CHD), colon cancer, and several other common and serious conditions. Although the definition of obesity typically relies on BMI, several studies suggest that, with respect to risk stratification, measurement of the waist-to-hip ratio (WHR) may be a superior predictor both of type 2 diabetes and CHD, possibly because of specific metabolic abnormalities accompanying central, rather than generalized, obesity (1,2). Both WHR and BMI are heritable traits, and various studies suggest that genes account for 25-70% of the observed variability (3,4).Melanocortin signaling in the hypothalamus plays a central role in the control of energy homeostasis. The proopiomelanocortin (POMC) gene is expressed in response to leptin signaling by neurons of the hypothalamic arcuate nucleus. Intracellular posttranslational processing of the POMC propeptide by prohormone convertase 2 leads to the production in these neurons of ␣-, ␤-, and ␥-melanocyte-stimulating hormones. These peptides signal to downstream target neurons in the lateral hypothalamus that express the melanocortin receptors MC3R and MC4R with resultant decrease in food intake and increase in energy expenditure (5). Rare mutations in the POMC gene cause monogenic, severe, early-onset obesity in humans; however, the influence of common polymorphisms in POMC on obesity phenotypes in less extreme individuals is unclear (6). POMC is also a precursor of adrenocorticotrophic hormone (ACTH); pathological ACTH excess results in severe central obesity. We have investigated the role of common polymorphisms of the POMC gene on abdominal obesity in a large family study. RESEARCH DESIGN AND METHODSSubject collection and phenotyping. The collect...

show abstract

“…The agouti-related protein (AGRP), produced in the arcuate nucleus, is an antagonist at the melanocortin 3 and 4 receptors (MC3-R and MC4-R), which are distributed throughout the brain. The proopiomelanocortin (POMC) products, such as ␣-melanocyte-stimulating hormone (␣-MSH), act as agonists at the melanocortin receptors (1)(2)(3). Hypothalamic POMC mRNA, AGRP mRNA, and the density of MC4-R have been shown to be altered with nutritional status (4,5).…”

mentioning

confidence: 99%

Effects of Chronic Central Nervous System Administration of Agouti-Related Protein in Pair-Fed Animals

Small

Kim²,

Stanley³

et al. 2001

Diabetes

144

View full text Add to dashboard Cite

The melanocortin receptor (MC3-R and MC4-R) antagonist, agouti-related protein (AGRP), is a potent stimulant of food intake. We examined the effect of chronic intracerebroventricular (ICV) AGRP treatment on energy metabolism and pituitary function in ad libitum fed rats and rats administered AGRP and then pair-fed to a saline control group. Chronic ICV AGRP (83-132) administration (1 nmol/day for 7 days) significantly increased food intake and body weight in ad libitum fed animals compared with saline-treated controls (body weight on day 7: 272 ± 6 [saline] vs. 319 ± 8 g [AGRP ad libitum fed]; P < 0.001). A significant increase in the epididymal fat pad weight, interscapular brown adipose tissue (BAT) weight, and plasma leptin was also observed in the ad libitum fed group. In the AGRP pair-fed group, a significant increase in the epididymal fat pad weight, BAT weight, and plasma leptin was again observed, suggesting that AGRP caused metabolic changes independent of increased food intake. BAT uncoupling protein 1 (UCP-1) content was significantly decreased compared with saline controls in both the AGRP ad libitum fed (21 ± 8% of saline control; P < 0.01) and AGRP pair-fed groups (24 ± 7% of saline control; P < 0.01). Plasma thyroid-stimulating hormone (TSH) was significantly suppressed compared with saline controls in both the AGRP ad libitum fed and AGRP pair-fed groups (3. T he hypothalamic melanocortin system is a regulator of energy homeostasis. The agouti-related protein (AGRP), produced in the arcuate nucleus, is an antagonist at the melanocortin 3 and 4 receptors (MC3-R and MC4-R), which are distributed throughout the brain. The proopiomelanocortin (POMC) products, such as ␣-melanocyte-stimulating hormone (␣-MSH), act as agonists at the melanocortin receptors (1-3). Hypothalamic POMC mRNA, AGRP mRNA, and the density of MC4-R have been shown to be altered with nutritional status (4,5). Defects of POMC processing and mutations of MC4-R in humans and mice are associated with gross obesity (6-11).5Administration of the synthetic MC3/4-R agonist MT II into the forebrain ventricles or directly into the paraventricular nucleus (PVN) of the hypothalamus of rats or mice produced a dosage-dependent reduction in food intake and body weight (12)(13)(14). A single injection of either the endogenous (AGRP ) or the synthetic (SHU9119 and HS014) MC3/4-R antagonists stimulated food intake in rodents (12,13,15,16). Chronic administration of the more selective MC4-R antagonist, HS028, for 7 days via an osmotic minipump significantly increased food intake and body weight. Tachyphylaxis to HS028 did not occur. However, neither energy expenditure nor pituitary function were examined in this study (17). Previous results from this department have demonstrated that AGRP (83-132), the endogenous hypothalamic melanocortin receptor antagonist, significantly increased 24-h food intake and antagonized the anorectic effects of ␣-MSH (16).The melanocortin system also influences energy expenditure. Intracerebroventricular (ICV) administra...

show abstract

The role of melanocortin signalling in the control of body weight: evidence from human and murine genetic models

Cited by 105 publications

References 65 publications

Monogenic Human Obesity Syndromes

Monogenic Human Obesity Syndromes

Association Between Common Polymorphisms of the Proopiomelanocortin Gene and Body Fat Distribution

Effects of Chronic Central Nervous System Administration of Agouti-Related Protein in Pair-Fed Animals

Contact Info

Product

Resources

About