ß3-Adrenergic-Receptor Gene Mutation Excites Obesity Researchers

ß₃-Adrenergic-Receptor Gene Mutation Excites Obesity Researchers

by David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period May- Jun 97	Rank Last Period Mar- Apr 97
1	R.V. Considine, et al., "Serum immunoreactive-leptin concentrations in normal-weight and obese humans," New Engl. J. Med., 334(5):292-5, 1 February 1996. [Thomas Jefferson U., Philadelphia, PA; Eli Lilly Res. Labs., Indianapolis, IN] *TV695	46	1
2	J. Shepherd, et al., "Prevention of coronary heart disease with prava-statin in men with hypercholesterolemia," New Engl. J. Med., 333(20):1301-7, 16 November 1995. [U. Glasgow, U.K.; Royal Infirm., Glasgow, U.K.; Dumfries & Galloway Dist. Gen. Hosp., Dumfries, U.K.] *TE365	43	2
3	M. Yoshiba, H. Okamoto, S. Mishiro, "Detection of the GBV-C hepatitis virus genome in serum from patients with fulminant hepatitis of unknown aetiology," The Lancet, 346(8983):1131-2, 28 October 1995. [Toshiba Gen. Hosp., Tokyo, Japan; Showa U., Yokohama, Japan; Jichi Med. Sch., Tochigi, Japan] *TB549	26	†
4	J.W. Mellors, et al., "Prognosis in HIV-1 infection predicted by the quantity of virus in plasma," Science, 272(5265):1167-70, 24 May 1996. [U. Pittsburgh, PA; Chiron Corp., Emeryville, CA] *UM889	25	4
5	F.M. Sacks, et al., "The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels," New Engl. J. Med., 335(14):1001-9, 3 October 1996. [8 U.S. and Canadian institutions] *VL459	24	†
6	U.A. Liberman, et al., "Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis," New Engl. J. Med., 333(22):1437-43, 30 November 1995. [12 institutions worldwide] *TG445	21	†
7	G.S. Omenn, et al., "Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease," New Engl. J. Med., 334(18):1150-5, 2 May 1996. [8 U.S. institutions] *UG831	21	9
8	G.A. Colditz, et al., "The use of estrogens and progestins and the risk of breast cancer in postmenopausal women," New Engl. J. Med., 332(24):1589-93, 15 June 1995. [Harvard Med. Sch., Boston, MA; Harvard Sch. Pub. Hlth., Boston, MA; Brigham and Women's Hosp., Boston, MA] *RC192	19	†
9	E. Widén, et al., "Association of a polymorphism in the ß₃-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns," New Engl. J. Med., 333(6):348-51, 10 August 1995. [U. Lund, Sweden; Helsinki U., Finland; Johns Hopkins U. Sch. Med., Baltimore, MD] *RN082	19	†
10	C.H. Hennekens, et al., "Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease," New Engl. J. Med., 334(18):1145-9, 2 May 1996. [Brigham and Women's Hosp., Boston, MA; Harvard Sch. Publ. Hlth., Boston, MA; Harvard Med. Sch., Boston, MA; U. Oxford, U.K.] *UG831	19	†

SOURCE: ISI's Hot Papers Database. Read the full legend.

It is not easy to persuade the general public (or indeed some physicians) that if there is a "fault" in obesity it lies at a metabolic, even genetic level and not in the character of those afflicted. If only the science was more straightforward. For example, the leptin story remains exciting both scientifically and in citation terms, and the paper highlighted in Science Watch two issues ago (8[3]:5, May/June 1997) is still on top this time (paper #1). Yet, apart from one familial case (see Nature, 387:903, 1997), mutations in the leptin gene remain elusive. Does the same disappointment await a missense mutation in the gene for the ß₃-adrenergic receptor?

This receptor in adipose tissue threads in and out of the cell several times, leaving three loops on the outside and three intracellular loops within. At position 64, at the beginning of the first intracellular loop, lies a mutation site (cytosine to thymidine) known as Trp64Arg. (Catecholamines, which adrenoreceptors are built to trap, have a role in lipolysis.) This mutation was the subject of three papers in the August 10, 1995, issue of the New England Journal of Medicine (333[6]). The article by Elisabeth Widn and her colleagues from Sweden and Finland reaches the Top Ten this time (see paper #9); one other is by Jeremy Walston, of the Johns Hopkins School of Medicine, Baltimore, and colleagues (pp. 343-7, #12, with 18 citations logged during May-June 1997); Karine Clment and colleagues, representing institutions in France and the United States, also have a "hot paper" that is not yet warm enough for e very top (pp. 352-4, with 15 citations for the period).

In the Clément study the mutation was found in only 14 of 185 obese people in France, and the allele frequencies were unremarkable at 0.08 (obese) and 0.10 (normal). Paper #12 is only indirectly about obesity, being a study of the diabetes-prone Pima Indians in the United States. The allele frequency was 0.31 and in the control groups it was around the 0.10 recorded in France. The impact of Trp64Arg was on the age of onset of non-insulin-dependent diabetes rather than on the risk of diabetes itself. In Bothnia, Finland (paper #9), and in the Pima, the frequency of the mutation was much the same in the diabetic as in the non-diabetic; the age of diabetes onset was lower, by five years, in the Pima Indians with Trp64Arg.

Johan Auwerx, of the Institut Pasteur de Lille, France, commented previously for Science Watch on the leptin paper at #1, so we went back to him about the ß₃ adrenoreceptor point mutation. He notes subsequent reports that have "failed to confirm the claims of the three NEJM papers," citing two reports in the Journal of Clinical Endocrinology and Metabolism from 1996 (81:4422-7; and 82:1284-7). "I would be very careful in interpreting results on the ß₃ adreno-receptor," Auwerx tells Science Watch. "Although undoubtedly important in the animal situation, good evidence for its importance in man is at best controversial at present."

There are significant increases in indicators of insulin resistance in the Finnish data, and Widn et al. speculate that premature cardiovascular mortality associated with this resistance explains why the expected difference in Trp64Arg allele frequency has not been found.

Auwerx thinks that the genes for the ß₃ adrenoreceptor and for leptin do have a role in body-weight homeostasis but "it is too early to tell their relative importance vis-ŕ-vis other players, including neuropeptide Y, sex steroids, glucocorticoids, and thyroid hormone." These two examples, he adds, "are a warning of the dangers of extrapolating from animal models, where obesity is largely monogenic, to human obesity, a polygenic disorder strongly influenced by environmental factors such as diet and exercise."

Mr. David W. Sharp, M.A. (Cambridge),
is a Deputy Editor of The Lancet, London, U.K.