Interindividual Variation in DNA Methylation at a Putative POMC Metastable Epiallele Is Associated with Obesity

Kühnen, Peter; Handke, Daniela; Waterland, Robert A.; Hennig, Branwen J.; Silver, Matt J.; Fulford, Anthony J. C.; Domínguez-Salas, Paula; Moore, Sophie E.; Prentice, Andrew M.; Spranger, Joachim; Hinney, Anke; Hebebrand, Johannes; Heppner, Frank L.; Walzer, Lena; Grötzinger, Carsten; Gromoll, Jörg; Wiegand, Susanna; Grüters, Annette; Krude, Heiko

doi:10.1016/j.cmet.2016.08.001

Cited by 118 publications

(92 citation statements)

References 33 publications

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“…These regions were first described in mice, but subsequent human studies in Gambia have demonstrated epigenetic variation at metastable epialleles that are linked to periconceptional maternal nutrition 77 , findings that have later been replicated in a rural Bangladeshi cohort 78 . The methylation status of metastable epialleles has been linked to later obesity and metabolic function 79 .…”

Section: Periconceptional Mechanismsmentioning

confidence: 99%

Adolescence and the next generation

Patton

Olsson

Skirbekk

et al. 2018

Nature

288

228

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Adolescent growth and social development shape the early development of offspring from preconception through to the post-partum period through distinct processes in males and females. At a time of great change in the forces shaping adolescence, including the timing of parenthood, investments in today’s adolescents, the largest cohort in human history, will yield great dividends for future generations.

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Section: Periconceptional Mechanismsmentioning

confidence: 99%

Adolescence and the next generation

Patton

Olsson

Skirbekk

et al. 2018

Nature

288

228

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“…Missense mutations in the POMC and MC4R genes are associated with severe hyperphagic obesity syndromes that manifests within the first 1–2 years of life (Farooqi and O'Rahilly, 2008). The central nervous melanocortin system responds to environmental cues through epigenetic modifications that have long-lasting effects on expression of genes promoting lean phenotypes (Benite-Ribeiro et al, 2016; Kühnen et al, 2016). Methylation in a variably methylated region (VMR) of the POMC gene allele is associated with altered body mass in humans (Kühnen et al, 2016).…”

Section: An Overview Of the Central Nervous Melanocortin Systemmentioning

confidence: 99%

“…The central nervous melanocortin system responds to environmental cues through epigenetic modifications that have long-lasting effects on expression of genes promoting lean phenotypes (Benite-Ribeiro et al, 2016; Kühnen et al, 2016). Methylation in a variably methylated region (VMR) of the POMC gene allele is associated with altered body mass in humans (Kühnen et al, 2016). Methylation of this region is sensitive to metabolic conditions in utero , and to paternal methylation patterns.…”

Section: An Overview Of the Central Nervous Melanocortin Systemmentioning

confidence: 99%

A Life without Hunger: The Ups (and Downs) to Modulating Melanocortin-3 Receptor Signaling

et al. 2017

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Melanocortin neurons conserve body mass in hyper- or hypo-caloric conditions by conveying signals from nutrient sensors into areas of the brain governing appetite and metabolism. In mice, melanocortin-3 receptor (MC3R) deletion alters nutrient partitioning independently of hyperphagia, promoting accumulation of fat over muscle mass. Enhanced rhythms in insulin and insulin-responsive metabolic genes during hypocaloric feeding suggest partial insulin resistance and enhanced lipogenesis. However, exactly where and how MC3Rs affect metabolic control to alter nutrient partitioning is not known. The behavioral phenotypes exhibited by MC3R-deficient mice suggest a contextual role in appetite control. The impact of MC3R-deficiency on feeding behavior when food is freely available is minor. However, homeostatic responses to hypocaloric conditioning involving increased expression of appetite-stimulating (orexigenic) neuropeptides, binge-feeding, food anticipatory activity (FAA), entrainment to nutrient availability and enhanced feeding-related motivational responses are compromised with MC3R-deficiency. Rescuing Mc3r transcription in hypothalamic and limbic neurons improves appetitive responses during hypocaloric conditioning while having minor effects on nutrient partitioning, suggesting orexigenic functions. Rescuing hypothalamic MC3Rs also restores responses of fasting-responsive hypothalamic orexigenic neurons in hypocaloric conditions, suggesting actions that sensitize fasting-responsive neurons to signals from nutrient sensors. MC3R signaling in ventromedial hypothalamic SF1(+ve) neurons improves metabolic control, but does not restore appetitive responses or nutrient partitioning. In summary, desensitization of fasting-responsive orexigenic neurons may underlie attenuated appetitive responses of MC3R-deficient mice in hypocaloric situations. Further studies are needed to identify the specific location(s) of MC3Rs controlling appetitive responses and partitioning of nutrients between fat and lean tissues.

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“…Genetic effects cannot explain these rapid population shifts in obesity, though they can help to explain which individuals within any given population will be more or less susceptible. Recent research has revealed that epigenetic effects may explain a much greater proportion of population variance than genetic effects [10,11] and this has implications for prevention as discussed below. The Demographic Switch in Social Groups Most Susceptible to Obesity…”

Section: The Emergence Of Overweight and Obesity Worldwidementioning

confidence: 99%

The Double Burden of Malnutrition in Countries Passing through the Economic Transition

Prentice¹

2018

Ann Nutr Metab

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Undernutrition in both its acute and chronic forms (wasting and stunting) is strongly inversely correlated with the wealth of nations. Consequently, as many low- and middle-income countries (LMICs) achieve economic advancement and pass through the so-called “nutrition transition,” their rates of undernutrition decline. Many countries successfully achieved the Millennium Development Goal of halving undernutrition and whole continents have been transformed in recent decades. The exception is Africa where the slower rates of decline in the prevalence of undernutrition has been overtaken by population growth so that the absolute number of stunted children is rising. In many regions, economic transition is causing a rapid increase in the number of overweight and obese people. The rapidity of this rise is such that many nations bear the simultaneous burdens of under- and overnutrition; termed the “double burden” of malnutrition. This double burden, accompanied as it is by the unfinished agenda of high levels of infectious diseases, is crippling the health systems of many LMICs and thus requires urgent attention. Although the prognosis looks threatening for many poor countries, they have the advantage of being able to learn from the mistakes made by other nations that have passed through the transition before them. Concerted action across many arms of government would achieve huge future dividends in health and wealth for any nations that can grasp the challenge.

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Interindividual Variation in DNA Methylation at a Putative POMC Metastable Epiallele Is Associated with Obesity

Cited by 118 publications

References 33 publications

Adolescence and the next generation

Adolescence and the next generation

A Life without Hunger: The Ups (and Downs) to Modulating Melanocortin-3 Receptor Signaling

The Double Burden of Malnutrition in Countries Passing through the Economic Transition

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