Association of β3-adrenoceptor polymorphism with obesity and diabetes: current status

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The initial findings

The pathogenesis of obesity and its associated metabolic complications, such as non-insulin-dependent diabetes mellitus, or its cardiovascular consequences, have been ascribed to a variety of environmental and genetic factors. Obesity results from an imbalance between caloric intake and energy expenditure. Adipose tissue plays a central role in regulating storage and mobilization of energy. Genes expressed preferentially in that tissue have thus been the focus of the search for inherited

Prevalence

World-wide screening studies (Table 1; 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26) revealed that the Arg64 mutant receptor is actually present in all the populations of the world, the only exception being the people of Naurua (Table 2; 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26, 27). In Pima Indians, the allelic frequency of the variant exceeds 30%, and it reaches 19% in the Japanese population. Several studies have

Association with higher weight gain and gender effect

Clément et al.[5] were the first to observe that, while the Arg64 form is not found at higher frequencies in Western obese individuals, its presence in such patients appears to result in an increased tendency to accumulate weight (Fig. 2). This finding has now been confirmed in various studies, particularly in those on women, where a resistance to weight loss was also observed[6]. This gender effect, increasingly highlighted by various groups8, 23, 26, led to the hypothesis of an advantage

Association with earlier onset non-insulin-dependent diabetes mellitus

Studies by Widen et al.[20]revealed that the presence of the Arg64 receptor variant could be associated with an earlier onset of non-insu- lin-dependent diabetes mellitus (NIDDM) in a Finnish population, an observation that had initially been made for the Pima Indians and Mexican Americans, and has now widely been confirmed in Japanese patients9, 10, 11.

Comparison of homozygous/ heterozygous carriers

The study of allelic frequencies and predicted numbers of carriers of the Arg64 form consistently suggests a lower than expected prevalence of homozygotes, possibly indicating that these individuals may have a decreased life expectancy except in Pima Indians[3]. At least one study[19] showed that increased BMI, insulin resistance and higher triglycerides were observed in homozygotes only.

Negative studies

While at least fifteen groups found some association between the presence of the Arg64 β3-adrenoceptor and symptoms of obesity or NIDDM, at least eight groups failed to find an association between the presence of the Arg64 form and higher BMI, age of onset of NIDDM, glucose or insulin levels7, 12, 13, 14, 18, 21, 24, 28 (Table 2).

These failures highlight the need to perform more and larger world-wide studies. Indeed, positive conclusions for 124 Mexican[5], 98 African[6] or 60 Chinese Americans

Biochemical effect

To evaluate the biochemical consequences of the Trp to Arg substitution, this change was introduced in the β3-adrenoceptor gene by the use of site-directed mutagenesis29, 30, and the resulting protein was studied in transfected cells. No change could be observed in the binding or adenylate cyclase activation properties of the Arg64 β3-adrenoceptor expressed in CHO cells or HEK293 cells29, 30. However, the absolute amounts of accumulated cAMP (Fig. 3) were considerably lower in the cells

Arg64 β3-adrenoceptor in other species

The comparison of the sequences of the β3-adrenoceptor of nine different species[2] reveals that all have an Arg residue at position 64 except the guinea-pig which has a Cys residue. However, the β3-adrenoceptor in this species does not appear to be expressed or to be functional in brown adipocytes, possibly suggesting that an Arg at position 64 is indeed a prerequisite for normal function[31]. The human receptor with a Trp64 would thus constitute the exception, and those individuals with the

Influence of other genetic traits

Human obesity is a multifactorial and multigenetic disease. It can therefore not be explained by a single substitution in one gene, as is the case f.i. in ob/ob mice lacking a functional leptin gene. In humans, various polymorphisms have now been found in several genes possibly involved in the development of obesity. These include β3-adrenoceptor, Uncoupling Protein (UCP) (see [32] for review) and more recently leptin[33](A. Strobel et al., unpublished). Various forms of obesity could be

Concluding remarks

To conclude, it thus appears that the single Trp to Arg substitution in the β3-adrenoceptor may indeed constitute a susceptibility factor to explain the onset of morbid obesity and NIDDM. In the Pima Indians, and possibly in Japanese, the variant is clearly more prevalent in obese than in non-obese individuals. In all other populations, the majority of studies have uncovered weak association, mostly in women, of the presence of the Arg64 variant with a number of symptoms related to the

Acknowledgements

Support for our work comes mostly from the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the University of Paris VII, and the Ministry for Research and Technology. We are also grateful for help from the Ligue Nationale contre le Cancer, the Fondation pour la Recherche Médicale Française and last but not least, the Association pour la Recherche contre le Cancer.

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