The impact of obesity-related SNP on appetite and energy intake

It is becoming increasingly recognized that early-life nutritional, metabolic and environmental factors can have a long-term impact on the early onset of obesity, type 2 diabetes and cardiovascular diseases. Numerous experimental and epidemiological observations support the concept that an individual's response to their adult lifestyle and nutritional environment depends not only on their genetic susceptibility but also on their previous early-life experiences. The current research challenge is to determine the primary pathways contributing to 'non- or epi-genetic' causes of excess adult weight gain and adiposity. Evidence from the fields of genetic epidemiology, life course modelling and diet-induced foetal programming all support a role for the FTO gene in this complex biological interaction. It may provide a missing link in the developmental regulation of energy metabolism. Our review therefore considers the role of the FTO gene in the early-life determination of body weight, body composition and energy balance. We will summarize current knowledge on FTO biology combining human genetic epidemiology, molecular models and findings from animal studies. Notably, we will focus on the role of FTO in energy balance in humans, the importance of FTO polymorphisms in childhood growth and the impact of foetal nutrition. Ultimately, we propose a new hypothesis for future research designed to understand the role of FTO in setting gene expression in metabolically active tissues.

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“…), fullness (Dougkas et al . ), eating frequency (McCaffery et al . ), hunger and satiety (Wardle et al .…”

Section: Biological and Physiological Roles Of Ftomentioning

confidence: 99%

Programming effects of FTO in the development of obesity

Sebért

Salonurmi

Keinänen‐Kiukaanniemi

et al. 2013

Acta Physiologica

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“…These genes included the leptin-coding gene LEP, the leptin receptor-coding gene LEPR, and the melanocortin-4 receptor-coding gene MC4R (Sarzynski et al, 2011;Dougkas et al, 2013). Previous studies have indicated that this pathway may be important for energy homeostasis (Balthasar et al, 2004(Balthasar et al, , 2005, while genetic studies have shown that mutations in certain genes involved in this pathway may express an obesity-causing phenotype.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of mutations in LEP, LEPR, and MC4R genes in individuals with severe obesity

Paolini¹,

Maltese²,

Ciondolo³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Obesity is a major public health concern; despite evidence of high heritability, the genetic causes of obesity remain unclear. In this study, we assessed the presence of mutations in three genes involved in the hypothalamic leptin-melanocortin regulation pathway (leptin, LEP; leptin receptor, LEPR; and melanocortin-4 receptor, MC4R), which is important for energy homeostasis in the body, in a group of patients with severe obesity. For this study, we selected 77 patients who had undergone bariatric surgery and had a pre-operative body mass index (BMI) >35 kg/m 2 , early onset and a family history of being overweight. Candidate genes were screened by direct sequence analysis to search for rare genetic variations. The common LEP -2548 G/A polymorphism was also evaluated for its influence on the BMI (in obesity patients) and for obesity risk, using a case-control study involving 117 healthy individuals. Two different non-synonymous alterations in MC4R were found in two patients: the p.(Thr112Met), previously described in the literature as a probable gene involved in the obesity phenotype, and the novel p.(Tyr302Asp) variant, predicted to be pathogenic by in silico evaluations and family segregation studies. The LEP -2548 G/A polymorphism was not associated with the BMI or obesity risk. In conclusion, we have reported a novel mutation in MC4R in a family of Italian patients with severe obesity. Screening for MC4R could be important for directing the carriers of mutations towards therapy including partial agonists of the MC4R that could normalize their appetite and inhibit compulsive eating. Next-generation sequencing could be used to clarify the genetic basis of obesity in the future.

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“…The FTO gene, consisting of nine exons, was located on chromosome 16q12.2 [10], that it encodes a 2-oxoglutarate-dependent nucleic acid demethylase and that it is located in the nucleus [11,12]. Polymorphisms in FTO gene have been determined as genetic risk factors for obesity [13]. Notably SNP rs9939609, located in intron 1, is associated with a 31 % increase in the risk of developing obesity [14].…”

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confidence: 99%