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Cited by 169Regulation of Appetite and ObesityGenetic Associations and EpidemiologyAdipokines, Inflammation, and Metabolic Diseases

The DOI matches its Crossref record; 74 of the 74 references it cites were found in a registry or an index.

Unraveling the Genetics of Human Obesity

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Mutch, David M., Clément, Karine·2006·PLoS Genetics
DOI 10.1371/journal.pgen.0020188PMC PMC1756898
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Abstract

The use of modern molecular biology tools in deciphering the perturbed biochemistry and physiology underlying the obese state has proven invaluable. Identifying the hypothalamic leptin/melanocortin pathway as critical in many cases of monogenic obesity has permitted targeted, hypothesis-driven experiments to be performed, and has implicated new candidates as causative for previously uncharacterized clinical cases of obesity. Meanwhile, the effects of mutations in the melanocortin-4 receptor gene, for which the obese phenotype varies in the degree of severity among individuals, are now thought to be influenced by one's environmental surroundings. Molecular approaches have revealed that syndromes (Prader-Willi and Bardet-Biedl) previously assumed to be controlled by a single gene are, conversely, regulated by multiple elements. Finally, the application of comprehensive profiling technologies coupled with creative statistical analyses has revealed that interactions between genetic and environmental factors are responsible for the common obesity currently challenging many Westernized societies. As such, an improved understanding of the different "types" of obesity not only permits the development of potential therapies, but also proposes novel and often unexpected directions in deciphering the dysfunctional state of obesity.

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Figure 1 The Leptin/Melanocortin Pathway The integration of signals from peripheral tissues in the hypothalamus is fundamental to the regulation of energy homeostasis. Distinct neuronal populations propagate the signaling of various molecules to control food intake and satiety. POMC neurons in the arcuate nucleus are activated by leptin and insulin and produce α-MSH, which then activates the MC4R receptor in the paraventricular nucleus, resulting in a satiety signal. The downstream roles of SIM1, BDNF, and TKRB are currently being explored. In contrast, a separate group of neurons expressing NPY and AGRP produce molecules that act as potent inhibitors of MC4R signaling. A dysfunction in these pathways will disrupt energy homeostasis. AGRP, agouti-related protein; α-MSH, alpha melanocyte stimulating hormone receptor; BDNF, brain-derived neurotropic factor; GHR, ghrelin receptor; ISR, insulin receptor; LepR, leptin receptor; NPY, neuropeptide Y; PC1 and 2, proconvertase 1 and 2; POMC, proopiomelanocortin; SIM1, single-minded homolog 1 (Drosophila); TRKB, tyrosine kinase receptor.
Figure 1 The Leptin/Melanocortin Pathway The integration of signals from peripheral tissues in the hypothalamus is fundamental to the regulation of energy homeostasis. Distinct neuronal populations propagate the signaling of various molecules to control food intake and satiety. POMC neurons in the arcuate nucleus are activated by leptin and insulin and produce α-MSH, which then activates the MC4R receptor in the paraventricular nucleus, resulting in a satiety signal. The downstream roles of SIM1, BDNF, and TKRB are currently being explored. In contrast, a separate group of neurons expressing NPY and AGRP produce molecules that act as potent inhibitors of MC4R signaling. A dysfunction in these pathways will disrupt energy homeostasis. AGRP, agouti-related protein; α-MSH, alpha melanocyte stimulating hormone receptor; BDNF, brain-derived neurotropic factor; GHR, ghrelin receptor; ISR, insulin receptor; LepR, leptin receptor; NPY, neuropeptide Y; PC1 and 2, proconvertase 1 and 2; POMC, proopiomelanocortin; SIM1, single-minded homolog 1 (Drosophila); TRKB, tyrosine kinase receptor.CC BY · PubMed Central
Figure 2 Gene–Environment Interactions in Common Obesity The complex interactions underlying polygenic obesity demonstrate that genetic, social, behavioral, and environmental factors are all capable of influencing the obese phenotype. The DNA strand should be interpreted as taking into account both genetic polymorphisms and the conformation of DNA structure (i.e., degree of methylation influenced by epigenetic events).
Figure 2 Gene–Environment Interactions in Common Obesity The complex interactions underlying polygenic obesity demonstrate that genetic, social, behavioral, and environmental factors are all capable of influencing the obese phenotype. The DNA strand should be interpreted as taking into account both genetic polymorphisms and the conformation of DNA structure (i.e., degree of methylation influenced by epigenetic events).CC BY · PubMed Central
Figure 3 Linkage Studies with Obesity-Related Phenotypes in Six Different Populations All chromosomes but the Y chromosome have been found linked with an obesity-related phenotype (e.g., body mass index, fat mass, waist circumference, and blood pressure) in a least one population. Links for relatively few regions have been replicated in more than one population, as illustrated by colored boxes stacked horizontally. The figure was created using information in the most recent Human Obesity Gene Map update [6]. The American population comprises Caucasian, Hispanic, African, and Asian Americans.
Figure 3 Linkage Studies with Obesity-Related Phenotypes in Six Different Populations All chromosomes but the Y chromosome have been found linked with an obesity-related phenotype (e.g., body mass index, fat mass, waist circumference, and blood pressure) in a least one population. Links for relatively few regions have been replicated in more than one population, as illustrated by colored boxes stacked horizontally. The figure was created using information in the most recent Human Obesity Gene Map update [6]. The American population comprises Caucasian, Hispanic, African, and Asian Americans.CC BY · PubMed Central

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Citations

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Metadata

Authors
Mutch, D. M., & Clément, K.
Affiliations
  • Inserm (FR)
  • University College London (GB)
Corresponding author
Clément, Karine
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2006
Volume
2
Issue
12
Pages
e188
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.0020188
PMC
PMC1756898
OpenAlex
W1977583120
Cited by
169
References
74
Citations by year
2026: 1 · 2023: 3 · 2022: 5 · 2021: 4 · 2020: 6 · 2019: 8 · 2018: 7 · 2017: 10 · 2016: 12 · 2015: 7 · 2014: 11 · 2013: 13 · 2012: 13
FWCI
1.43
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Keywords
human obesity, monogenic obesity, leptin, melanocortin pathway, melanocortin-4 receptor, Prader-Willi syndrome, Bardet-Biedl syndrome, gene-environment interaction, obesity phenotypes, obesity treatment
MeSH terms
Animals, Chromosome Mapping, Environment, Humans, Hypothalamus, Mutation, Obesity, Phenotype, Syndrome, Gene Expression Profiling

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