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Relation of the multilocus genetic composite reflecting high dopamine signaling capacity to future increases in BMI.

ABSTRACT: Because food intake exerts its rewarding effect by increasing dopamine (DA) signaling in reward circuitry, it theoretically follows that individuals with a greater number of genotypes putatively associated with high DA signaling capacity are at increased risk for overeating and subsequent weight gain. We tested the association between the multilocus genetic composite risk score, defined by the total number of genotypes putatively associated with greater DA signaling capacity (i.e. TaqIA A2 allele, DRD2-141C Ins/Del and Del/Del genotypes, DRD4-S allele, DAT1-S allele, and COMT Val/Val genotype), and future increases in Body Mass Index (BMI) in three prospective studies. Participants in Study 1 (N?=?30; M age?=?15.2; M baseline BMI?=?26.9), Study 2 (N?=?34; M age?=?20.9; M baseline BMI?=?28.2), and Study 3 (N?=?162; M age?=?15.3, M baseline BMI?=?20.8) provided saliva samples from which epithelial cells were collected, permitting DNA extraction. The multilocus genetic composite risk score was associated with future increases in BMI in all three studies (Study 1, r?=?0.37; Study 2, r?=?0.22; Study 3, r?=?0.14) and the overall sample (r?=?0.19). DRD4-S was associated with increases in BMI in Study 1 (r?=?0.42), Study 2 (r?=?0.27), and in the overall sample (r?=?0.17). DAT1-S was associated with increases in BMI in Study 3 (r?=?0.17) and in the overall sample (r?=?0.12). There were no associations between the other genotypes (TaqIA, COMT, and DRD2-141C) and change in BMI over 2-year follow-up. Data suggest that individuals with a genetic propensity for greater DA signaling capacity are at risk for future weight gain and that combining alleles that theoretically have a similar function may provide a more reliable method of modeling genetic risk associated with future weight gain than individual genotypes.

SUBMITTER: Yokum S

PROVIDER: S-EPMC4333052 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Relation of the multilocus genetic composite reflecting high dopamine signaling capacity to future increases in BMI.

Yokum Sonja S Marti C Nathan CN Smolen Andrew A Stice Eric E

Appetite 20141215

Because food intake exerts its rewarding effect by increasing dopamine (DA) signaling in reward circuitry, it theoretically follows that individuals with a greater number of genotypes putatively associated with high DA signaling capacity are at increased risk for overeating and subsequent weight gain. We tested the association between the multilocus genetic composite risk score, defined by the total number of genotypes putatively associated with greater DA signaling capacity (i.e. TaqIA A2 allel ...[more]

PMID: 25523644

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Project description:BackgroundThe prevalence of obesity has increased dramatically worldwide. The obesity epidemic begs for novel concepts and therapeutic targets that cohesively address "food-abuse" disorders. We demonstrate a molecular link between impairment of a central kinase (Akt) involved in insulin signaling induced by exposure to a high-fat (HF) diet and dysregulation of higher order circuitry involved in feeding. Dopamine (DA) rich brain structures, such as striatum, provide motivation stimuli for feeding. In these central circuitries, DA dysfunction is posited to contribute to obesity pathogenesis. We identified a mechanistic link between metabolic dysregulation and the maladaptive behaviors that potentiate weight gain. Insulin, a hormone in the periphery, also acts centrally to regulate both homeostatic and reward-based HF feeding. It regulates DA homeostasis, in part, by controlling a key element in DA clearance, the DA transporter (DAT). Upon HF feeding, nigro-striatal neurons rapidly develop insulin signaling deficiencies, causing increased HF calorie intake.Methodology/principal findingsWe show that consumption of fat-rich food impairs striatal activation of the insulin-activated signaling kinase, Akt. HF-induced Akt impairment, in turn, reduces DAT cell surface expression and function, thereby decreasing DA homeostasis and amphetamine (AMPH)-induced DA efflux. In addition, HF-mediated dysregulation of Akt signaling impairs DA-related behaviors such as (AMPH)-induced locomotion and increased caloric intake. We restored nigro-striatal Akt phosphorylation using recombinant viral vector expression technology. We observed a rescue of DAT expression in HF fed rats, which was associated with a return of locomotor responses to AMPH and normalization of HF diet-induced hyperphagia.Conclusions/significanceAcquired disruption of brain insulin action may confer risk for and/or underlie "food-abuse" disorders and the recalcitrance of obesity. This molecular model, thus, explains how even short-term exposure to "the fast food lifestyle" creates a cycle of disordered eating that cements pathological changes in DA signaling leading to weight gain and obesity.

Dataset Information

Relation of the multilocus genetic composite reflecting high dopamine signaling capacity to future increases in BMI.

Publications

Relation of the multilocus genetic composite reflecting high dopamine signaling capacity to future increases in BMI.

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