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Resistance to the Lipolytic Action of Epinephrine: A New Feature of Protein G_s Deficiency

Department of Pediatric Endocrinology and INSERM U342 (J.C.C., C.L.S, L.C., J.L.C., P.B.), and CNRS UPR 1524 (L.C., M.G.), Hôpital Saint Vincent de Paul, 75014 Paris, France; Department of Pediatrics (E.M.), Hôpital Charles Nicolle, 76000 Rouen, France; and Centre de Recherche (P.A.), Groupe LIPHA, 91380 Chilly-Mazarin, France

Address correspondence and requests for reprints to: Dr. Jean-Claude Carel, INSERM U342, Hôpital Saint Vincent de Paul 82 av Denfert Rochereau, 75014 Paris, France. E-mail: carel{at}cochin.inserm.fr

	Abstract

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Deficiency of protein G_s (Gs; OMIM no.103580), the stimulatory regulator of adenylyl cyclase, is associated with resistance to PTH and other hormones, sc calcifications, short stature, and skeletal defects (Albright’s hereditary osteodystrophy). It is caused by heterozygous loss of function mutations in GNAS1, the gene encoding the -subunit of G_s. Obesity is a classical feature of patients with G_s deficiency, but the mechanism leading to fat accumulation has not been elucidated. We measured glycerol flux, using a nonradioactive tracer dilution approach, to analyze the lipolytic response to epinephrine in 6 patients with G_s deficiency and PTH resistance and compared it to six age-matched normal controls and nine massively obese children. Basal glycerol production was reduced by 50%, and lipolytic response to epinephrine was reduced by 67%, in G_s-deficient children, as compared with controls. The degree of impairment of lipolysis was similar in G_s-deficient children who were only moderately overweight and in morbidly obese children. These findings extend the spectrum of hormonal resistance in G_s deficiency. Besides ß-adrenergic receptors, G_s protein itself should be examined as a possible step involved in the decreased lipolysis observed in common obesity.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
DEFICIENCY of protein G_s (G_s), the stimulatory regulator of adenylyl cyclase, is associated with heterogeneous clinical manifestations. Although resistance to PTH was the first reported feature, further studies revealed resistance to other hormones (TSH, gonadotropins, glucagon), as well as additional manifestations: sc calcifications, Albright’s hereditary osteodystrophy, hearing impairment, and some degree of mental retardation (OMIM no.103580; for review, see Refs. 1, 2). Genetic analysis revealed heterozygous loss of function mutation in GNAS1, the gene encoding the -subunit of G_s (3, 4, 5, 6, 7, 8), transmitted as an autosomal dominant trait with incomplete penetrance.

A striking feature of the disease is the variability of the clinical and biochemical abnormalities, not explained by the various molecular defects of the protein. Also of interest is the persistence of normal distal responses to some of the hormones signaling through G_s (such as vasopressin and glucagon). Obesity is a classical feature of patients with G_s deficiency (1), but the mechanism leading to fat accumulation has not been elucidated (9, 10, 11). Mobilization of fat stores occurs in adipose tissue through the hydrolysis of triglycerides into glycerol and fatty acids (lipolysis). While insulin has a powerful antilipolytic effect, catecholamines are the major hormones stimulating triglyceride hydrolysis in man (12). The effects of catecholamines are initiated by binding to lipolytic ß-adrenoreceptors and antilipolytic ₂-adrenoreceptors in white adipose tissue (12). Activated adrenoreceptors regulate adenylate cyclase activity, cAMP production, and protein kinase A, resulting in phosphorylation and activation of hormone-sensitive lipase, which breaks down triglycerides to glycerol and free fatty acids (FFA), via di- and monoacylglycerol intermediates (13). In a recent in vivo study of obese children in the dynamic phase of obesity, we found that the lipolytic effect of catecholamines was markedly decreased, supporting a role for catecholamine resistance in the increased fat accumulation (14). A resistance of lipolysis to catecholamines was also found in abdominal sc fat cells of normal-weight first-degree relatives of obese adults (15), suggesting that this alteration could be a primary mechanism.

Because obesity is frequently associated with G_s deficiency and G_s is part of the pathway transducing the lipolytic signal through ß-adrenergic receptors, we tested whether epinephrine resistance was part of the spectrum of hormonal resistance in patients with G_s deficiency. We found that patients with G_s deficiency are resistant to the lipolytic actions of epinephrine.

	Subjects and Methods

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Subjects (Table 1)

Six children (four boys, two girls), with G_s deficiency were studied. Two of them (one boy, one girl) were sibs. The initial manifestations of G_s deficiency was hypocalcemia (5/6) or short stature and dysmorphic features (1/6). All patients had clinical features of Albright’s hereditary osteodystrophy (in particular, short fourth and fifth metacarpals) and decreased erythrocyte G_s activity (63 ± 3%; range, 50–73%). All six patients had PTH resistance and were treated with vitamin D at the time of the study; 5/6 had TSH resistance and were treated with L-T₄. They were compared to six normal children (four boys, two girls) and nine obese children (four boys, five girls) recruited according to approval of the institutional ethical committee, as described in (14). Because the results in obese children have already been published (14), only the baseline data and glycerol flux data will be presented here, since they were studied with the same methodology as were Gs-deficient children.

All subjects consumed an isocaloric standard diet 72 hr before the study. Studies were performed at 0800 h, following an overnight 12-h fast. After collection of a baseline sample, infusion of the [1,1,2,3,3-²H₅] glycerol tracer (ISOTEC, Miamisburg, OH) began with a priming dose, followed by continuous infusion at a constant rate of 0.063 ± 0.003 µmol x kg^-1 x min^-1 for 3 hr. In controls, insulin was infused at a minimal rate of 0.20 mU/kg x min, starting with glycerol infusion, to reach a plasma level of insulin comparable with G_s-deficient children, whereas plasma glucose was maintained nearly constant (16, 17). Epinephrine infusion started at 60 min, at a rate of 0.75 µg/min for 60 min, then at 1.5 µg/min for another 60-min period. Epinephrine doses were similar for G_s-deficient and lean children and were calculated to induce lipolysis while minimally stimulating the cardiovascular system, according to previous studies in adult men (18, 19, 20). Blood samples (for the measurement of plasma glycerol concentration, [²H₅] enrichment, plasma FFA, leptin, epinephrine, norepinephrine, and insulin) were taken at baseline and at 10-min intervals during the last 30 min of the two study periods.

Analytical procedures and calculations

Details on the assays for plasma FFA, insulin, epinephrine, norepinephrine, and glycerol [²H₅] enrichment have been reported (14). Ra, the rate of appearance of endogenous glycerol in plasma, and Rd (the rate of its disposal) were quantified in basal conditions and during the epinephrine infusion. Because individual glycerol concentrations and enrichments varied within less than 10% of mean value during the last 20 min of each 60-min study period, we used a steady-state dilution equation to calculate glycerol turnover (see Ref. 24). Ra and Rd were equal and expressed in µmol/min to figure whole-body glycerol fluxes. Glycerol release was normalized to fat mass, as recommended (21, 22). Erythrocyte G_s activity was measured as described (23) and was expressed as percent of an internal standard (normal > 83%).

Statistical analysis

Data are presented as mean ± SE. Statistical comparison between groups was performed with a two-tailed Student’s t test for unpaired data. The relationship between variables was evaluated using simple linear regression analysis. To compare the response of each variable (glycerol flux, plasma FFA, heart rate, or plasma glucose) to epinephrine between subjects, we used the standard two stages (STS) (NIH) method described by Feldman (24). For each individual (i), we calculated the slopes of the regression lines (variable) = ßi·(epinephrine) + i. The slope of such a regression line, ßi, represents the proportional increase of the variable, in response to a unit change in epinephrine. The means ± SE of these slopes were calculated and compared between G_s-deficient and control children, by unpaired t test.

	Results

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Plasma substrates and hormones

Basal state. Basal plasma glycerol, glucose, and FFA concentrations were comparable in G_s-deficient and control children (Table 2, data not shown for obese children). In G_s-deficient children, plasma epinephrine was 197 ± 48 pg/mL vs. 150 ± 22 pg/mL in normal children (not significant, NS) and 299 ± 62 in obese children (P < 0.025 vs. lean children). Plasma norepinephrine was 412 ± 107 pg/mL in G_s-deficient patients and 1507 ± 256 pg/mL in normal children (P < 0.005). Plasma leptin and insulin were higher in obese and G_s-deficient children, as expected from their increased body mass index (BMI).

Glycerol production (Fig. 1)

Basal. Basal glycerol production was lower in G_s-deficient (146 ± 18 µmol/min or µmol·min^-1 and obese (176 ± 25 µmol/min or µmol·min^-1) than in control children (294 ± 35 µmole/min or µmol·min^-1; respectively, P < 0.005 and P < 0.02, Fig. 1A). This difference persisted after normalization to adipose tissue mass, revealing that glycerol release per unit fat mass was 49% lower in G_s-deficient (9.3 ± 0.8 µmol·min^-1·kg fat mass^-1) and 65% lower in obese (6.3 ± 1.1 µmol·min^-1··kg fat mass^-1) than in control children (18.2 ± 1.4 µmol·min^-1·kg fat mass^-1, P < 0.0005 vs. both groups, Fig. 1B).

View larger version (15K): [in this window] [in a new window]   Figure 1. Glycerol release in response to epinephrine. A, Dose-response curve of lipolytic rate (glycerol release) expressed in µmol·min-1; closed circles, lean controls; closed squares, Gs-deficient children; open squares, obese children; P < 0.02, Gs-deficient vs. lean; P < 0.002, obese vs. lean; NS, Gs-deficient vs. obese by the STS (NIH) method. B, Dose response curve of lipolytic rate (glycerol release) expressed in µmol·min-1·kg fat mass-1.

Heart rate (Table 2)

The resting heart rate was significantly higher in G_s-deficient patients (68 ± 4 vs. 58 ± 2, P < 0.05). During epinephrine infusion, the relative increase of heart rate was 115% and 132% of basal value in control children, consistent with the expected effects of small doses of epinephrine (18, 19, 20). In G_s-deficient patients, the increase was only 105% and 112%. The mean ß-slope of the individual regression equations (heart rate = ßi [Epi] + i) was 0.035 ± 0.006 in G_s-deficient and 0.063 ± 0.011 in control children (P = 0.051). Therefore, the chronotropic response to epinephrine seems to be slightly (or not) affected by G_s deficiency.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The present data indicate that, in G_s-deficient children, the mobilization of triglyceride stores, per unit of fat mass, is decreased by approximately 50% in the basal state. Elevation of epinephrine levels within the physiological range (488 ± 60 and 397 ± 42 pg/mL in G_s-deficient and control children, respectively) resulted in a markedly increased glycerol production in control children, contrasting with the resistance observed in G_s-deficient children. Although we could not perform a complete dose-response curve of glycerol release to serum epinephrine in vivo, our results suggest that both the maximal response and the ED50 were diminished in the G_s-deficient children.

Our patients were mildly overweight (123 ± 5% of ideal body weight; range, 107- 141%) and were compared to a group of lean children (similar fat mass, lower BMI) and to a group of obese children with much higher BMI and fat mass. Under epinephrine stimulation, the slope of response of glycerol production was similarly reduced in obese (-73% vs. controls) and in G_s-deficient (-67% vs. controls) patients, and the dose response curve of these two groups on Fig. 1A looks very similar. This indicates that, in obese and Gs-deficient individuals, the capacity of adipose tissue to respond to a similar increment of epinephrine is markedly decreased, even though most of our Gs-deficient patients do not reach the commonly accepted threshold used to define obesity. The expression of data per kg of fat mass shows that fluxes are further reduced in massively obese children but that the slope is still similar in both pathological groups (Fig. 1B). Previous studies of adrenergic response in patients with pseudohypoparathyroidism (PHP) (9, 10) have investigated heterogeneous groups of adult patients with decreased or normal erythrocyte G_s activity, i.e. patients that would now be classified, respectively, as PHP Ia or Ib (2). These studies have concluded at a blunted cAMP response and a normal FFA response to isoproterenol. Similarly, a blunted stimulatory response of adenylate cyclase was observed in the plasma membranes of adipocytes from four patients with PHP Ia and decreased erythrocyte G_s activity (11). Our studies, in a more homogeneous group of patients with G_s deficiency and PHP Ia, indicate that the end organ response to adrenergic stimulation is markedly decreased and might contribute to the obesity frequently observed in these patients. However, our patients were only mildly overweight, suggesting that, at least in children, regulatory pathways limit the expansion of body fat mass. For instance, insulin sensitivity at the adipose tissue level could counterbalance the detrimental effect of epinephrine resistance, a hypothesis that can be tested (17).

The clinical picture of G_s deficiency is extremely variable, even in individuals of the same family, known to harbor the same mutation. Part of this variability could be caused by imprinting of the GNAS1 gene (25), but no direct evidence has been obtained in the human so far (26, 27). In the mouse, tissue-specific imprinting of Gnas, the mouse homolog of GNAS1, has been demonstrated in knockout mice with a null allele of Gnas (28). In addition to paternal imprinting in the renal cortex (the site of PTH action), but not in the renal medulla, Gnas was paternally imprinted in the brown and white adipose tissue. Heterozygous mice, inheriting the null allele from the mother, accumulated fat and became obese in early adulthood. Oppositely, mice inheriting the null allele from their father were leaner than normal, a situation dissimilar to the humans, where patients with paternal inheritance of Albright’s hereditary osteodystrophy tend to also be obese. Further studies should address the question of adipocyte response to epinephrine in vivo and in vitro in individuals with Albright’s hereditary osteodystrophy and normal PTH response (pseudo-PHP).

Decreased lipolytic activity has been implicated in common obesity, both in adults and in children. However, the mechanisms leading to a decreased activity of the key regulatory enzyme, hormone-sensitive lipase are not known (29). Studies in abdominal sc fat cells of relatives of obese adults suggest that this impairment lies downstream of cAMP production (15). Other studies point towards a decreased function of ß-adrenergic receptors in common obesity. The level of expression of ß₂ receptors (30), as well as molecular variants of the ß₂ (31) and ß₃ receptors (32, 33, 34, 35, 36), have been discussed as possible mechanisms associated with obesity. Both ß₁ and ß₂ receptors are readily detectable on white adipose tissue in humans, whereas the expression of the ß₃ receptor is low, detectable only by reverse transcriptase PCR (37, 38). The respective roles of these three receptors in epinephrine-induced lipolysis are still debated. Recent studies, using selective ß₃-adrenergic receptor agonists in primate and human white adipose tissue, suggest that ß₃ receptors might be major mediators of the lipolytic action of epinephrine (39). In our patients, G_s deficiency, a step that has not been considered in common obesity, is expected to reduce signal transduction from all types of ß-adrenergic receptors and could phenocopy other defects encountered in more common forms of obesity. In addition, it is conceivable that decreased G_s activity or mutations in GNAS1 could be implicated in common obesity, in the absence of the characteristic multihormonal resistance observed in PHP. In vitro data also support the fact that quantitative variations of G_s alter the efficacy of signal transduction to adenylyl cyclase (40, 41).

In conclusion, the lipolytic response to epinephrine is markedly decreased in patients with G_s deficiency and PTH resistance, extending the spectrum of hormonal resistance in G_s deficiency. Our findings also point out regulatory mechanisms preventing the massive accumulation of fat in these patients, at least during childhood. Besides ß-adrenergic receptors, G_s protein itself should be examined as a possible step involved in the decreased lipolysis observed in common obesity.

	Acknowledgments

 
We thank Michèle Lotton for the clinical studies of the obese children, and Drs. Laclyde and Guillien for referral of the patients.

Received January 5, 1999.

Revised July 20, 1999.

Accepted July 28, 1999.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Spiegel AM. 1989 Pseudohypoparathyroidism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited diseases. 6th ed. New York: McGraw-Hill; 2013–2027.
2. Weinstein LS. 1998 Albright hereditary osteodystrophy, pseudohypoparathyroidism and Gs deficiency. In: Spiegel AM, ed. Contemporary Endocrinology: G proteins, receptors and disease. Totowa, NJ: Humana Press; 23–56.
3. Patten JL, Johns DR, Valle D, et al. 1990 Mutations in the gene encoding the stimulatory G protein of adenylate cyclase in Albright’s hereditary osteodystrophy. N Engl J Med. 322:1412–1418.[Abstract]
4. Weinstein LS, Gejman PV, Friedman E, et al. 1990 Mutations of the Gs alpha subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis. Proc Natl Acad Sci USA. 87:8287–8290.[Abstract/Free Full Text]
5. Weinstein LS, Gejman PV, de Mazancourt P, American N, Spiegel AM. 1992 A heterozygous 4-bp deletion mutation in the Gs alpha gene (GNAS1) in a patient with Albright hereditary osteodystrophy. Genomics. 13:1319–1321.[CrossRef][Medline]
6. Miric A, Vechio JD, Levine MA. 1993 Heterogeneous mutations in the gene encoding the alpha-subunit of the stimulatory G protein of adenylyl cyclase in Albright hereditary osteodystrophy. J Clin Endocrinol Metab. 76:1560–1568.[Abstract]
7. Weinstein LS, Shenker A. 1993 G protein mutations in human disease. Clin Biochem. 26:333–338.[CrossRef][Medline]
8. Farfel Z, Iiri T, Shapira H, Roitman A, Mouallem M, Bourne HR. 1996 Pseudohypoparathyroidism, a novel mutation in the betagamma-contact region of Gs alpha impairs receptor stimulation. J Biol Chem. 271:19653–19655.[Abstract/Free Full Text]
9. Carlson HE, Brickman AS, Burns TW, Langley PE. 1985 Normal free fatty acid response to isoproterenol in pseudohypoparathyroidism. J Clin Endocrinol Metab. 61:382–384.[Abstract/Free Full Text]
10. Carlson HE, Brickman AS. 1983 Blunted plasma cyclic adenosine monophosphate response to isoproterenol in pseudohypoparathyroidism. J Clin Endocrinol Metab. 56:1323–1326.[Abstract/Free Full Text]
11. Kaartinen JM, Kaar ML, Ohisalo JJ. 1994 Defective stimulation of adipocyte adenylate cyclase, blunted lipolysis, and obesity in pseudohypoparathyroidism 1a. Pediatr Res. 35:594–597.[Medline]
12. Lafontan M, Berlan M. 1993 Fat cell adrenergic receptors and the control of white and brown fat cell function. J Lipid Res. 34:1057–1091.[Abstract]
13. Frayn KN, Coppack SW, Fielding BA, Humphreys SM. 1995 Coordinated regulation of hormone-sensitive lipase and lipoprotein lipase in human adipose tissue in vivo: implications for the control of fat storage and fat mobilization. Adv Enzyme Regul. 35:163–178.[CrossRef][Medline]
14. Bougneres P, Le Stunff C, Pecqueur C, Pinglier E, Adnot P, Ricquier D. 1997 In vivo resistance of lipolysis to epinephrine. A new feature of childhood onset obesity. J Clin Invest. 99:2568–2573.[Medline]
15. Hellstrom L, Langin D, Reynisdottir S, Dauzats M, Arner P. 1996 Adipocyte lipolysis in normal weight subjects with obesity among first-degree relatives. Diabetologia. 39:921–928.[Medline]
16. Le Stunff C, Bougneres PF. 1992 Glycerol production and utilization during the early phase of human obesity. Diabetes. 41:444–450.[Abstract]
17. Le Stunff C, Bougneres P. 1994 Early changes in postprandial insulin secretion, not in insulin sensitivity, characterize juvenile obesity. Diabetes. 43:696–702.[Abstract]
18. Galster AD, Clutter WE, Cryer PE, Collins JA, Bier DM. 1981 Epinephrine plasma thresholds for lipolytic effects in man: measurements of fatty acid transport with [l-13C]palmitic acid. J Clin Invest. 67:1729–1738.
19. Lupien JR, Hirshman MF, Horton ES. 1990 Effects of norepinephrine infusion on in vivo insulin sensitivity and responsiveness. Am J Physiol. 259:E210–E215.
20. Arner P, Engfeldt P, Nowak J. 1981 In vivo observations on the lipolytic effect of noradrenaline during therapeutic fasting. J Clin Endocrinol Metab. 53:1207–1212.[Abstract/Free Full Text]
21. Wolfe RR, Peters EJ, Klein S, Holland OB, Rosenblatt J, Gary Jr H. 1987 Effect of short-term fasting on lipolytic responsiveness in normal and obese human subjects. Am J Physiol. 252:E189–E196.
22. Jensen MD. 1991 Regulation of forearm lipolysis in different types of obesity. In vivo evidence for adipocyte heterogeneity. J Clin Invest. 87:187–193.
23. Marguet C, Basuyau JP, Brunelle P, Fessard C, Mallet E. 1992 GTP-dependent protein(Gs) activity in preterm infants. Biol Neonate. 62:113–119.[CrossRef][Medline]
24. Feldman HA. 1988 Families of lines: random effects in linear regression analysis. J Appl Physiol. 64:1721–1732.[Abstract/Free Full Text]
25. Davies SJ, Hughes HE. 1993 Imprinting in Albright’s hereditary osteodystrophy. J Med Genet. 30:101–103.[Abstract/Free Full Text]
26. Wilson LC, Oude-Luttikhuis ME, Clayton PT, Fraser WD, Trembath RC. 1994 Parental origin of Gs alpha gene mutations in Albright’s hereditary osteodystrophy. J Med Genet. 31:835–839.[Abstract/Free Full Text]
27. Campbell R, Gosden CM, Bonthron DT. 1994 Parental origin of transcription from the human GNAS1 gene. J Med Genet. 31:607–614.[Abstract/Free Full Text]
28. Yu S, Yu D, Lee E, et al. 1998 Variable and tissue-specific hormone resistance in heterotrimeric Gs protein alpha-subunit (Gs alpha) knockout mice is due to tissue-specific imprinting of the Gs alpha gene. Proc Natl Acad Sci USA . 95:8715–8720.[Abstract/Free Full Text]
29. Langin D, Holm C, Lafontan M. 1996 Adipocyte hormone-sensitive lipase: a major regulator of lipid metabolism. Proc Nutr Soc. 55:93–109.[Medline]
30. Reynisdottir S, Wahrenberg H, Carlstrom K, Rossner S, Arner P. 1994 Catecholamine resistance in fat cells of women with upper-body obesity due to decreased expression of beta 2-adrenoceptors. Diabetologia. 37:428–435.[Medline]
31. Large V, Hellstrom L, Reynisdottir S, et al. 1997 Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function. J Clin Invest. 100:3005–3013.[Medline]
32. Widen E, Lehto M, Kanninen T, Walston J, Shuldiner AR, Groop LC. 1995 Association of a polymorphism in the beta 3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns. N Engl J Med. 333:348–351.[Abstract/Free Full Text]
33. Walston J, Silver K, Bogardus C, et al. 1995 Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the beta 3-adrenergic-receptor gene. N Engl J Med. 333:343–347.[Abstract/Free Full Text]
34. Clement K, Vaisse C, Manning BS, et al. 1995 Genetic variation in the beta 3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity. N Engl J Med. 333:352–354.[Abstract/Free Full Text]
35. Gagnon J, Mauriege P, Roy S, et al. 1996 The Trp64Arg mutation of the beta 3 adrenergic receptor gene has no effect on obesity phenotypes in the Quebec Family Study and Swedish Obese Subjects cohorts. J Clin Invest. 98:2086–2093.[Medline]
36. Mitchell BD, Blangero J, Comuzzie AG, et al. 1998 A paired sibling analysis of the beta-3 adrenergic receptor and obesity in Mexican Americans. J Clin Invest. 101:584–587.[Medline]
37. Tavernier G, Barbe P, Galitzky J, et al. 1996 Expression of beta3-adrenoceptors with low lipolytic action in human subcutaneous white adipocytes. J Lipid Res. 37:87–97.[Abstract]
38. Giacobino JP. 1995 Beta 3-adrenoceptor: an update. Eur J Endocrinol. 132:377–385.[Abstract/Free Full Text]
39. Fisher MH, Amend AM, Bach TJ, et al. 1998 A selective human ß-3 adrenergic receptor agonist increases metabolic rate in rhesus monkeys. J Clin Invest. 101:2387–2393.[Medline]
40. Krumins AM, Barber R. 1997 Examination of the effects of increasing Gs protein on beta 2-adrenergic receptor, Gs, and adenylyl cyclase interactions. Biochem Pharmacol. 54:61–72.[CrossRef][Medline]
41. Yang X, Lee FY, Wand GS. 1997 Increased expression of Gs (alpha) enhances activation of the adenylyl cyclase signal transduction cascade. Mol Endocrinol. 11:1053–1061.[Abstract/Free Full Text]
42. Sempé M, Pédron G, Roy P. 1979 Auxologie, méhodes et séquences. Paris: Théraplix;

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