Allosteric regulation of the calcium-sensing receptor in obese individuals

He,Yonghan; Perry,Ben; Bi,Mingxin; Sun,Hui; Zhao,Tiantian; Li,Ying; Sun,Changhao

doi:10.3892/ijmm.2013.1408

Allosteric regulation of the calcium-sensing receptor in obese individuals

Authors:
- Yonghan He
- Ben Perry
- Mingxin Bi
- Hui Sun
- Tiantian Zhao
- Ying Li
- Changhao Sun
View Affiliations

Affiliations: National Key Discipline of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China, Aquatic and Crop Resource Development, Life Sciences Branch, National Research Council Canada, Charlottetown, Prince Edward Island C1A 4P3, Canada, Emergency Department, The Second Afﬁliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China, Department of Psychology, University of Toronto, Toronto, Ontario M1C 1A4, Canada
Published online on: June 5, 2013 https://doi.org/10.3892/ijmm.2013.1408
Pages: 511-518

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

We have previously reported that the calcium-sensing receptor (CaSR) plays an important role in modulating lipid metabolism under low calcium conditions. The aim of this study was to identify possible regulators of CaSR and the mechanisms of action of CaSR in obese individuals. Subcutaneous fat samples were obtained from 10 obese and 10 non-obese males undergoing elective abdominal surgery. Visceral fat pads were obtained from 12 obese and 12 non‑obese male rats. Serum lipid, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) concentrations, as well as the gene and protein expression of CaSR in the white adipose tissue of obese subjects and rats were determined. Serum total calcium, vitamin D, parathyroid hormone (PTH) and amino acid levels in human subjects were measured. Intracellular calcium and cyclic adenosine monophosphate (cAMP) levels in rat adipocytes were measured by laser scanning confocal microscopy and ELISA, respectively. The results revealed that serum triglyceride (TG), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), TNF-α, IL-6 and PTH levels were significantly higher in the obese individuals versus the controls. By contrast, serum vitamin D and amino acid concentrations were lower in the obese individuals versus the controls. In addition, intracellular calcium levels were higher, while cAMP levels were lower in the obese rat adipocytes compared with the control group. However, the gene and protein expression of CaSR in white adipose tissue did not differ between the obese groups and the controls. Thus, these results suggest that CaSR functions not through its expression, but rather through allosteric regulation in obese individuals.

View Figures

View References

1	Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser. 894:i–xii. 1–253. 2000.PubMed/NCBI
2	Kopelman PG: Obesity as a medical problem. Nature. 404:635–643. 2000.PubMed/NCBI
3	Brown EM and MacLeod RJ: Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev. 81:239–297. 2001.PubMed/NCBI
4	Brown EM, Gamba G, Riccardi D, et al: Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature. 366:575–580. 1993.
5	Cifuentes M, Albala C and Rojas C: Calcium-sensing receptor expression in human adipocytes. Endocrinology. 146:2176–2179. 2005. View Article : Google Scholar : PubMed/NCBI
6	Cifuentes M and Rojas CV: Antilipolytic effect of calcium-sensing receptor in human adipocytes. Mol Cell Biochem. 319:17–21. 2008. View Article : Google Scholar : PubMed/NCBI
7	He Y, Zhang H, Teng J, Huang L, Li Y and Sun C: Involvement of calcium-sensing receptor in inhibition of lipolysis through intracellular cAMP and calcium pathways in human adipocytes. Biochem Biophys Res Commun. 404:393–399. 2011. View Article : Google Scholar : PubMed/NCBI
8	He YH, He Y, Liao XL, et al: The calcium-sensing receptor promotes adipocyte differentiation and adipogenesis through PPARgamma pathway. Mol Cell Biochem. 361:321–328. 2012. View Article : Google Scholar : PubMed/NCBI
9	He YH, Song Y, Liao XL, et al: The calcium-sensing receptor affects fat accumulation via effects on antilipolytic pathways in adipose tissue of rats fed low-calcium diets. J Nutr. 141:1938–1946. 2011. View Article : Google Scholar
10	Hofer AM and Brown EM: Extracellular calcium sensing and signalling. Nat Rev Mol Cell Biol. 4:530–538. 2003. View Article : Google Scholar
11	Chen RA and Goodman WG: Role of the calcium-sensing receptor in parathyroid gland physiology. Am J Physiol Renal Physiol. 286:F1005–F1011. 2004. View Article : Google Scholar : PubMed/NCBI
12	Draznin B, Sussman KE, Eckel RH, Kao M, Yost T and Sherman NA: Possible role of cytosolic free calcium concentrations in mediating insulin resistance of obesity and hyperinsulinemia. J Clin Invest. 82:1848–1852. 1988. View Article : Google Scholar : PubMed/NCBI
13	Draznin B, Sussman K, Kao M, Lewis D and Sherman N: The existence of an optimal range of cytosolic free calcium for insulin-stimulated glucose transport in rat adipocytes. J Biol Chem. 262:14385–14388. 1987.PubMed/NCBI
14	Byyny RL, LoVerde M, Lloyd S, Mitchell W and Draznin B: Cytosolic calcium and insulin resistance in elderly patients with essential hypertension. Am J Hypertens. 5:459–464. 1992.PubMed/NCBI
15	Conigrave AD, Mun HC and Lok HC: Aromatic L-amino acids activate the calcium-sensing receptor. J Nutr. 137(6 Suppl 1): S1524–S1527. 2007.PubMed/NCBI
16	Emanuel RL, Adler GK, Kifor O, et al: Calcium-sensing receptor expression and regulation by extracellular calcium in the AtT-20 pituitary cell line. Mol Endocrinol. 10:555–565. 1996.PubMed/NCBI
17	Brown AJ, Zhong M, Finch J, et al: Rat calcium-sensing receptor is regulated by vitamin D but not by calcium. Am J Physiol. 270:F454–F460. 1996.PubMed/NCBI
18	Brown AJ, Ritter CS, Finch JL and Slatopolsky EA: Decreased calcium-sensing receptor expression in hyperplastic parathyroid glands of uremic rats: role of dietary phosphate. Kidney Int. 55:1284–1292. 1999. View Article : Google Scholar : PubMed/NCBI
19	Antuna-Puente B, Feve B, Fellahi S and Bastard JP: Adipokines: the missing link between insulin resistance and obesity. Diabetes Metab. 34:2–11. 2008. View Article : Google Scholar : PubMed/NCBI
20	Calabro P, Golia E, Maddaloni V, et al: Adipose tissue-mediated inflammation: the missing link between obesity and cardiovascular disease? Intern Emerg Med. 4:25–34. 2009. View Article : Google Scholar : PubMed/NCBI
21	Cifuentes M, Fuentes C, Mattar P, et al: Obesity-associated proinflammatory cytokines increase calcium sensing receptor (CaSR) protein expression in primary human adipocytes and LS14 human adipose cell line. Arch Biochem Biophys. 500:151–156. 2010. View Article : Google Scholar
22	Cifuentes M, Fuentes C, Tobar N, et al: Calcium sensing receptor activation elevates proinflammatory factor expression in human adipose cells and adipose tissue. Mol Cell Endocrinol. 361:24–30. 2012. View Article : Google Scholar
23	Sung RY, Lau P, Yu CW, Lam PK and Nelson EA: Measurement of body fat using leg to leg bioimpedance. Arch Dis Child. 85:263–267. 2001. View Article : Google Scholar : PubMed/NCBI
24	Nunez C, Gallagher D, Visser M, Pi-Sunyer FX, Wang Z and Heymsfield SB: Bioimpedance analysis: evaluation of leg-to-leg system based on pressure contact footpad electrodes. Med Sci Sports Exerc. 29:524–531. 1997. View Article : Google Scholar : PubMed/NCBI
25	Li Y, Wang C, Zhu K, Feng RN and Sun CH: Effects of multivitamin and mineral supplementation on adiposity, energy expenditure and lipid profiles in obese Chinese women. Int J Obes (Lond). 34:1070–1077. 2010. View Article : Google Scholar : PubMed/NCBI
26	Huang L, Xue J, He Y, et al: Dietary calcium but not elemental calcium from supplements is associated with body composition and obesity in Chinese women. PLoS One. 6:e277032011. View Article : Google Scholar : PubMed/NCBI
27	Li LM, Rao KQ, Kong LZ, et al: A description on the Chinese national nutrition and health survey in 2002. Zhonghua Liu Xing Bing Xue Za Zhi. 26:478–484. 2005.(In Chinese).
28	Reeves PG, Nielsen FH and Fahey GC Jr: AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr. 123:1939–1951. 1993.PubMed/NCBI
29	Friedewald WT, Levy RI and Fredrickson DS: Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 18:499–502. 1972.PubMed/NCBI
30	Niu YC, Feng RN, Hou Y, et al: Histidine and arginine are associated with inflammation and oxidative stress in obese women. Br J Nutr. 108:57–61. 2012. View Article : Google Scholar : PubMed/NCBI
31	Rodbell M: Metabolism of isolated fat cells. I Effects of hormones on glucose metabolism and lipolysis. J Biol Chem. 239:375–380. 1964.PubMed/NCBI
32	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001.
33	Kimball S, Fuleihan Gel H and Vieth R: Vitamin D: a growing perspective. Crit Rev Clin Lab Sci. 45:339–414. 2008. View Article : Google Scholar : PubMed/NCBI
34	Abdullah HI, Pedraza PL, Hao S, Rodland KD, McGiff JC and Ferreri NR: NFAT regulates calcium-sensing receptor-mediated TNF production. Am J Physiol Renal Physiol. 290:F1110–F1117. 2006. View Article : Google Scholar : PubMed/NCBI
35	Wang D, Pedraza PL, Abdullah HI, McGiff JC and Ferreri NR: Calcium-sensing receptor-mediated TNF production in medullary thick ascending limb cells. Am J Physiol Renal Physiol. 283:F963–F970. 2002. View Article : Google Scholar : PubMed/NCBI
36	Canaff L and Hendy GN: Calcium-sensing receptor gene transcription is up-regulated by the proinflammatory cytokine, interleukin-1beta. Role of the NF-kappaB pathway and kappaB elements. J Biol Chem. 280:14177–14188. 2005. View Article : Google Scholar : PubMed/NCBI
37	Nielsen PK, Rasmussen AK, Butters R, et al: Inhibition of PTH secretion by interleukin-1 beta in bovine parathyroid glands in vitro is associated with an up-regulation of the calcium-sensing receptor mRNA. Biochem Biophys Res Commun. 238:880–885. 1997. View Article : Google Scholar : PubMed/NCBI
38	Toribio RE, Kohn CW, Capen CC and Rosol TJ: Parathyroid hormone (PTH) secretion, PTH mRNA and calcium-sensing receptor mRNA expression in equine parathyroid cells, and effects of interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha on equine parathyroid cell function. J Mol Endocrinol. 31:609–620. 2003. View Article : Google Scholar
39	Park HS, Park JY and Yu R: Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-alpha and IL-6. Diabetes Res Clin Pract. 69:29–35. 2005. View Article : Google Scholar : PubMed/NCBI
40	Brown AJ, Zhong M, Ritter C, Brown EM and Slatopolsky E: Loss of calcium responsiveness in cultured bovine parathyroid cells is associated with decreased calcium receptor expression. Biochem Biophys Res Commun. 212:861–867. 1995. View Article : Google Scholar : PubMed/NCBI
41	Yao JJ, Bai S, Karnauskas AJ, Bushinsky DA and Favus MJ: Regulation of renal calcium receptor gene expression by 1,25-dihydroxyvitamin D₃ in genetic hypercalciuric stone-forming rats. J Am Soc Nephrol. 16:1300–1308. 2005. View Article : Google Scholar : PubMed/NCBI
42	Parikh SJ, Edelman M, Uwaifo GI, et al: The relationship between obesity and serum 1,25-dihydroxy vitamin D concentrations in healthy adults. J Clin Endocrinol Metab. 89:1196–1199. 2004. View Article : Google Scholar : PubMed/NCBI
43	Andersen T, McNair P, Hyldstrup L, et al: Secondary hyperparathyroidism of morbid obesity regresses during weight reduction. Metabolism. 37:425–428. 1988. View Article : Google Scholar : PubMed/NCBI
44	Bell NH, Epstein S, Greene A, Shary J, Oexmann MJ and Shaw S: Evidence for alteration of the vitamin D-endocrine system in obese subjects. J Clin Invest. 76:370–373. 1985. View Article : Google Scholar : PubMed/NCBI
45	Bell NH, Epstein S, Shary J, Greene V, Oexmann MJ and Shaw S: Evidence of a probable role for 25-hydroxyvitamin D in the regulation of human calcium metabolism. J Bone Miner Res. 3:489–495. 1988. View Article : Google Scholar : PubMed/NCBI
46	Conigrave AD, Franks AH, Brown EM and Quinn SJ: L-amino acid sensing by the calcium-sensing receptor: a general mechanism for coupling protein and calcium metabolism? Eur J Clin Nutr. 56:1072–1080. 2002. View Article : Google Scholar : PubMed/NCBI
47	Ni Z, Smogorzewski M and Massry SG: Effects of parathyroid hormone on cytosolic calcium of rat adipocytes. Endocrinology. 135:1837–1844. 1994.PubMed/NCBI
48	Shi H, Norman AW, Okamura WH, Sen A and Zemel MB: 1alpha,25-Dihydroxyvitamin D₃ modulates human adipocyte metabolism via nongenomic action. FASEB J. 15:2751–2753. 2001.PubMed/NCBI
49	Xue B, Greenberg AG, Kraemer FB and Zemel MB: Mechanism of intracellular calcium ([Ca²⁺]i) inhibition of lipolysis in human adipocytes. FASEB J. 15:2527–2529. 2001.
50	Zemel MB, Shi H, Greer B, Dirienzo D and Zemel PC: Regulation of adiposity by dietary calcium. FASEB J. 14:1132–1138. 2000.PubMed/NCBI