Dietary calcium and body weight: what's the “skinny”?

Abstract

There has been growing interest in mechanisms underlying the observation that high dietary calcium intake may attenuate weight gain. Both animal and human studies have explored this association [[1]Zemel M.B. Regulation of adiposity and obesity risk by dietary calcium: mechanisms and implications.J Am Coll Nutr. 2002; 21: 146S-151SCrossref PubMed Scopus (295) Google Scholar]. However, the metabolic alterations that explain this phenomenon remain unclear, as are the molecular mechanisms that may be at play. This month's article by Zhang et al provides new insights into this question. Dietary calcium has been suggested to play an important role in the regulation of energy metabolism. In one study whose primary aim was to explore the relation between blood pressure and nutrient intake, a significant inverse correlation was noted between calcium intake and body weight [[3]McCarron D.A. Morris C.D. Henry H.J. Stanton J.L. Blood pressure and nutrient intake in the United States.Science. 1984; 224: 1392-1398Crossref PubMed Scopus (573) Google Scholar]. Two other studies have shown inverse correlations between circulating ionized Ca2+ and body mass index in obese individuals [4Andersen T. McNair P. Fogh-Andersen N. Nielson T.T. Hyldstruo L. Transbol I. Increased parathyroid hormone as a consequence of changed complex binding of plasma calcium in morbid obesity.Metabolism. 1986; 35: 147-151Abstract Full Text PDF PubMed Scopus (53) Google Scholar, 5Lind L. Lithell H. Hvarfner A. Pollare T. Ljunghall S. The relationships between mineral metabolism, obesity and fat distribution.Eur J Clin Invest. 1993; 23: 307-310Crossref PubMed Scopus (44) Google Scholar]. Other studies found that high-calcium diets are associated with decreased lipid accretion and weight gain during periods of excessive dietary consumption, including evidence of increased lipolysis, which thereby may accelerate weight loss [[1]Zemel M.B. Regulation of adiposity and obesity risk by dietary calcium: mechanisms and implications.J Am Coll Nutr. 2002; 21: 146S-151SCrossref PubMed Scopus (295) Google Scholar]. However, the underlying mechanisms remain largely unclear. Calcium may attenuate the direct effects of vitamin D on lipid metabolism within adipocytes, which may explain in part the effects of dietary calcium in countering obesity [6Shi H. Zemel M.B. Effects of dietary calcium on adipocyte lipid metabolism and body weight regulation in energy restricted aP2-agouti transgenic mice.FASEB J. 2001; 15: 291-293PubMed Google Scholar, 7Bruckbauer A.G.J. Rekapalli B. Zemel M.S. The effects of dairy components on energy partitioning and metabolic risk in mice: a microarray study.J Nutrigenet Nutrigenomics. 2009; 2: 64-77Crossref PubMed Scopus (15) Google Scholar]. Other effects of calcium include alterations in metabolic efficiency, increased core temperature, and expression of the adipocyte uncoupling protein 2 [[6]Shi H. Zemel M.B. Effects of dietary calcium on adipocyte lipid metabolism and body weight regulation in energy restricted aP2-agouti transgenic mice.FASEB J. 2001; 15: 291-293PubMed Google Scholar]. In a 2-year prospective study of 54 normal-weight women who participated in an exercise intervention, the ratio of dietary calcium to energy was a significant negative predictor of changes in both body weight and body fat [[8]Lin Y.C. Lyle R.M. McCabe R.D. McCabe G.P. Weaver C.M. Teegarden D. Dairy calcium is related to changes in body composition during a two-year exercise intervention in young women.J Am Coll Nutr. 2000; 19: 754-760Crossref PubMed Scopus (203) Google Scholar]. In addition, increased total calcium and dairy calcium intakes in these subjects predicted fat mass reductions independent of caloric intake for women consuming a lower-energy diet (ie, less than a mean of 1876 kcal/d). In children, a significant inverse correlation has also been reported between dietary calcium and body fat in a 5-year longitudinal study of preschool children [[9]Carruth B.R. Skinner J.D. The role of dietary calcium and other nutrients in moderating body fat in preschool children.Int J Obes. 2001; 25: 559-566Crossref PubMed Scopus (252) Google Scholar]. In a final study of 780 women who participated in 5 clinical trials, significant negative associations were found between calcium intake and body weight for subjects during the third, fifth, and eighth decades of life [[10]Davies K.M. Heaney R.P. Recker R.R. Lappe J.M. Barger-Lux M.J. Rafferty K. et al.Calcium intake and body weight.J Clin Endocrinol Metab. 2000; 85: 4635-4638Crossref PubMed Scopus (363) Google Scholar]. Overall, the investigators conclude that a calcium intake of 1000 mg/d is associated with an 8-kg reduction in body weight. The role of vitamin D in relation to this topic is important to consider. There has been interest in whether 1,25-dihydroxyvitamin D (1,25[OH]2D) stimulates calcium influx within adipocytes, leading to the eventual stimulation of lipogenesis, inhibition of lipolysis, and expanded adipocyte triglyceride stores [[1]Zemel M.B. Regulation of adiposity and obesity risk by dietary calcium: mechanisms and implications.J Am Coll Nutr. 2002; 21: 146S-151SCrossref PubMed Scopus (295) Google Scholar]. If this hypothesis were true, suppressing 1,25(OH)2D concentrations through provision of dietary calcium would be assumed to inhibit adiposity and promote weight loss. What data support a relationship between 1,25(OH)2D and obesity? First, vitamin D receptor gene polymorphisms (eg, D12S85) may influence insulin secretion and an individual's susceptibility to diabetes [11McDermott M.F. Ramachandran A. Ogunkolade B.W. Aganna E. Curtis D. Boucher B.J. et al.Allelic variations in the vitamin D receptor influences susceptibility to IDDM in Indian Asians.Diabetologia. 1997; 40: 971-975Crossref PubMed Scopus (163) Google Scholar, 12Hitman G.A. Mannan N. McDermott M.F. Aganna E. Ogunkolade B.W. Hales C.N. et al.Vitamin D receptor gene polymorphisms influence insulin secretion in Bangladeshi Asians.Diabetes. 1998; 47: 688-690Crossref PubMed Scopus (121) Google Scholar]. This polymorphism is also associated with susceptibility to obesity in patients with early-onset type 2 diabetes mellitus [[13]Ye W.Z. Reis A. Dubois-Laforgue D. Bellanne-Chantelot C. Timsait J. Velho G. Vitamin D receptor gene polymorphisms are associated with obesity in type II diabetic subjects with early age of onset.Eur J Endocrinol. 2001; 145: 181-186Crossref PubMed Scopus (130) Google Scholar], and circulating 1,25(OH)2D levels have also been reported to be elevated in obese individuals [14Bell N.H. Epstein S. Greene A. Shary J. Oexmann M.J. Shaw S. Evidence for alteration of the vitamin D–endocrine system in obese subjects.J Clin Invest. 1985; 76: 370-373Crossref PubMed Scopus (508) Google Scholar, 15Kerstetter J. Cabellero B. O'Brien K. Wurtman R. Allen L. Mineral homeostasis in obesity: effects of euglycemic hyperinsulinemia.Metabolism. 1991; 40: 707-713Abstract Full Text PDF PubMed Scopus (41) Google Scholar, 16Anderson T. McNair P. Hyldstrup L. Fogh A.N. Nielsen T.T. Astrup A. et al.Secondary hyperparathyroidism of morbid obesity regresses during weight reduction.Metabolism. 1988; 37: 425-428Abstract Full Text PDF PubMed Scopus (48) Google Scholar]. 1,25-Dihydroxyvitamin D–induced hyperinsulinemia may be a primary contributor to obesity, as 1,25(OH)2D appears to serve as an insulin secretogogue [17Kajikawa M. Ishida H. Fujimoto S. Mukai E. Nishimura M. Fujita J. et al.An insulinotropic effect of vitamin D analog with increasing intracellular Ca2+ concentration in pancreatic B cells through nongenomic signal transduction.Endocrinology. 1999; 140: 4706-4712Crossref PubMed Google Scholar, 18Norman A.W. Frankel B.J. Heldt A.M. Grodsky G.M. Vitamin D deficiency inhibits pancreatic secretion of insulin.Science. 1980; 209: 823-825Crossref PubMed Scopus (572) Google Scholar, 19Tanaka Y. Seino Y. Ishida M. Yamaoka K. Satomura K. Yabuuchi H. et al.Effect of 1,25-dihydroxyvitamin D3 on insulin secretion: direct of mediated?.Endocrinology. 1986; 118: 1971-1976Crossref PubMed Scopus (35) Google Scholar, 20Jain R. von Hurst P.R. Stonehouse W. Love D.R. Higgins C.M. Coad J. Association of vitamin D receptor gene polymorphisms with insulin resistance and response to vitamin D.Metabolism. 2011; ([Epub ahead of print])PubMed Google Scholar, 21Li H.W. Brereton R.E. Anderson R.A. Wallace A.M. Ho C.K. Vitamin D deficiency is common and associated with metabolic risk factors in patients with polycystic ovary syndrome.Metabolism. 2011; ([Epub ahead of print])Google Scholar]. Vitamin D may also function to counter resistance to both leptin and insulin that is seen in an obese individual. Although vitamin D deficiency is known to cause hyperparathyroidism, one study found the association to be present primarily in individuals with elevated leptin levels. These data suggest that leptin may be a critical important modifier of this effect, consistent with 25-OH-vitamin D–mediated inhibition of leptin [[22]Maetani M. Maskarinec G. Franke A.A. Cooney R.V. Association of leptin, 25-hydroxyvitamin D, and parathyroid hormone in women.Nutr Cancer. 2009; 61: 225-231Crossref PubMed Scopus (57) Google Scholar]. Another study supported the role of vitamin D in weight management, as vitamin D3 and retinoic acid powerfully inhibited in vitro leptin secretion by human adipose tissue [[23]Menendez C. Lage M. Peino R. Baldelli R. Concheiro P. Diéguez C. et al.Retinoic acid and vitamin D(3) powerfully inhibit in vitro leptin secretion by human adipose tissue.J Endocrinol. 2001; 170: 425-431Crossref PubMed Scopus (102) Google Scholar]. Leptin is well known to be a key regulator of metabolic, neuroendocrine, and immune function in humans [24Chan J.L. Matarese G. Shetty G.K. et al.Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans.PNAS. 2006; 103: 8481-8486Crossref PubMed Scopus (144) Google Scholar, 25Mantzoros C.S. Flier J.S. Leptin as a therapeutic agent—trials and tribulations.J Clin Endocrinol Metab. 2000; 85: 4000-4002Crossref PubMed Scopus (107) Google Scholar]. Leptin's response to both calcium and vitamin D supplementation, especially in the context of obesity and weight loss, is interesting to consider. In the article by Zhang et al [[2]Zhang R. Zhu W. Du X. Xin J. Xue Y. Zhang Y. et al.S100A16 mediation of weight gain attenuation induced by dietary calcium.Metabolism. 2012; 61: 157-163Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar] in this month's issue of Metabolism, the authors used a diet-induced obese rat model produced by feeding the rodents a high-fat diet. The study examined the expression and functional role of the signaling protein, S100A16, in the obese rats fed a diet high in both fat and calcium. Forty animals were randomly divided into 4 groups by diet, each provided for 8 weeks: normal diet; high fat, normal calcium; high fat, high calcium; and high fat, low calcium. Body weight and visceral fat were significantly attenuated in those rodents receiving the high-fat, high-calcium diet. That group of rodents also exhibited decreased serum triglyceride and total cholesterol concentrations. In addition, expression of S100A16 was significantly decreased in the high-fat, high-calcium group. Elevation of intracellular calcium via calcium ionophores led to exclusion of nuclear S100A16. In parallel experiments, overexpression of S100A16 in cultured 3T3-L1 preadipocytes enhanced adipogenesis, but a significant reduction in Akt phosphorylation was also detected. Thus, in the 3T3-L1 adipocytes, insulin-stimulated signaling was negatively influenced by increased expression of S100A16. Taken together, these results suggest that a high-calcium diet may lead to the nuclear exclusion of S100A16 that ultimately results in inhibition of adipogenesis and enhanced insulin sensitivity. However, some questions regarding the mechanisms that mediated these findings still remain. What is known about S100 proteins? These are small acidic proteins (10-13 kd in size) that possess a distinctive homo- or heterodimeric structure and 2 highly conserved calcium-binding domains. Because of their elevated expression in tumor tissue, S100 proteins are considered to be cancer biomarkers. However, altered expression of S100 proteins has been associated with a variety of diseases in addition to cancer, including psoriasis, melanoma, and neurodegenerative diseases, among others [26Fritz G. Botelho H.M. Morozova-Roche L.A. Gomes C.M. Natural and amyloid self-assembly of S100 proteins: structural basis of functional diversity.FEBS J. 2010; 277: 4578-4590Crossref PubMed Scopus (98) Google Scholar, 27Rezvanpour A. Shaw G.S. Unique S100 target protein interactions.Gen Physiol Biophys. 2009; 28: F39-F46Crossref PubMed Scopus (6) Google Scholar, 28Jury C.S. McAllister E.J. MacKie R.M. Rising levels of serum S100 protein precede other evidence of disease progression in patients with malignant melanoma.Br J Dermatol. 2000; 143: 269-274Crossref PubMed Scopus (81) Google Scholar]. S100A16 is a novel member of the S100 family, with ubiquitous expression, but of unclear significance as to its physiological function within specific tissues [29Sturchler E. Cox J.A. Durussel I. Weibel M. Heizmann C.W. S100A16, a novel calcium-binding protein of the EF-hand superfamily.J Biol Chem. 2006; 281: 38905-38917Crossref PubMed Scopus (54) Google Scholar, 30Marenholz I. Heizmann C.W. Fritz G. S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature).Biochem Biophys Res Commun. 2004; 322: 1111-1122Crossref PubMed Scopus (661) Google Scholar]. Of relevance to this study, S100A16 is highly expressed in adipocytes. There is also some evidence that S100A16 interacts in immunoprecipitation assays with p53 [[31]Yun Liu R.Z. Jing S. Sun Y. Li J. Wei D. Zhao A.Z. Identification of S100A16 as a novel adipogenesis promoting factor in 3T3-L1 cells.Endocrinology. 2011; 152: 903-911Crossref PubMed Scopus (38) Google Scholar], a tumor suppressor protein known to be a negative regulator of adipogenesis but a positive regulator of insulin sensitivity [32Olovnikov I.A. Kravchenko J.E. Chumakov P.M. Homeostatic functions of the p54 tumor suppressor: regulation of energy metabolism and antioxidant defense.Semin Cancer Biol. 2009; 19: 32-41Crossref PubMed Scopus (122) Google Scholar, 33Constance C.M. Morgan 4th, J.I. Umek R.M. C/EBPalpha regulation of the growth-arrest–associated gene gadd45.Mol Cell Biol. 1996; 16: 3878-3883Crossref PubMed Google Scholar, 34Hallenborg P. Feddersen S. Madsen L. Kristiansen K. The tumor suppressors pRB and p53 as regulators of adipocyte differentiation and function.Expert Opin Ther Targets. 2009; 13: 235-246Crossref PubMed Scopus (49) Google Scholar]. Therefore, whether increased calcium intake results in decreased interaction of S100A16 with p53 is speculated in this article and is an intriguing possibility and remains to be directly tested in future studies. Both strengths and limitations of the study by Zhang et al[[2]Zhang R. Zhu W. Du X. Xin J. Xue Y. Zhang Y. et al.S100A16 mediation of weight gain attenuation induced by dietary calcium.Metabolism. 2012; 61: 157-163Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar] need to be considered. First, the authors formulate hypotheses on a subject of high interest that spans many fields and disciplines. Both basic scientists and clinical investigators are keenly interested in whether calcium intake is involved in the regulation of body weight. The animal model they developed is novel, and the experiments were rigorously designed with meticulous attention to multiple end points. Regarding limitations, the number of rats studied was small, limiting the statistical power with which conclusions could be drawn. Independent studies are needed to see if the current results can be replicated. As with any study of rodents, findings that were observed remain to be ultimately translated to human physiology. It can also be difficult in studies of rodents to determine whether the doses of nutrients (such as calcium and fat) studied in the experimental model can later be feasibly provided as part of a human diet. It is also difficult to determine whether the doses of calcium that resulted in S100A16 alterations in rodents studied will result in changes in this protein in humans. Nonetheless, the results are thought-provoking and hopefully will stimulate additional work in this area, one of particular importance given the rising incidence of obesity, insulin resistance, and the metabolic syndrome across the age spectrum. Outside of the weight and obesity field, the topic of calcium intake and, in particular, calcium supplementation has become an area of intense controversy. Calcium is needed, in combination with vitamin D, for normal skeletal growth and repair; it is essential for normal bone turnover and remodeling [35Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10300) Google Scholar, 36Huh H.Y. Gordon C.M. Vitamin D deficiency in children and adolescents: epidemiology, impact and treatment.Rev Endocr Metab Disord. 2008; 9: 161-170Crossref PubMed Scopus (114) Google Scholar]. A deficiency of calcium can lead to rickets and other metabolic bone disorders, whereas excessive consumption can lead to hypercalcemia, hypercalciuria, and, ultimately, renal stones and nephrocalcinosis. There has been recent concern that calcium supplementation may increase the risk for myocardial infarction, a topic that has spurred fierce debate. The issue under discussion is the fact that calcium may, theoretically, be harmful to blood vessels in excessive doses because it may complex with phosphorus on the endothelial surface to induce vascular calcification. In a study that has received much recent press, Bolland et al [[37]Bolland M.J. Barber P.A. Doughty R.N. et al.Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial.BMJ. 2008; 336: 262-266Crossref PubMed Scopus (556) Google Scholar] suggested that an increased risk of cardiovascular events occurred in the calcium- vs placebo-supplemented adults. Their Kaplan-Meier survival curves suggested greater negative effects of calcium supplementation on cardiovascular outcomes that became more substantial with longer duration of follow-up. However, others, including a group from Western Australia, have questioned the validity of these findings. They conducted a prospective, placebo-controlled trial of 1460 women 75 years and older who were receiving calcium carbonate supplementation [38Prince R.L. Devine A. Dhaliwal S.S. Dick I.M. Effects of calcium supplementation on clinical fracture and bone structure: results of a 5 year, double-blind, placebo-controlled trial in elderly women.Arch Intern Med. 2006; 166: 869-875Crossref PubMed Scopus (378) Google Scholar, 39Lewis J.R. Calver J. Zhu K. Flicker L. Prince R.L. Calcium supplementation and the risks of atherosclerotic vascular disease in older women: results of a 5-year RCT and a 4.5 year follow-up.J Bone Miner Res. 2011; 26: 35-41Crossref PubMed Scopus (164) Google Scholar]. There was no risk of increased cardiovascular risk at 5 years among the outcomes studied. Opposing views related to this issue are now hotly debated, the undercurrent of the arguments being whether one would trade lower body weight for an increased risk of myocardial ischemia or other cardiovascular event! More clinical studies are needed, especially longitudinal cohort studies or trials that assess health outcomes in supplemented vs nonsupplemented individuals. Although calcium intake is often considered in the context of bone health and osteoporosis prevention, this study suggests that dietary calcium is also of importance in the regulation of energy metabolism. These results suggest that high-calcium diets lead to inhibition of adipogenesis and enhanced insulin sensitivity via a signaling mechanism mediated by S100A16. This is an intriguing finding that will undoubtedly spur further research. At a time when the obesity epidemic is growing, dietary manipulation such as an increase in calcium intake represents a simple intervention that may result in substantial rewards on a public health level. Therefore, it will be important to continue to pursue “the skinny” on the link between calcium intake and weight control.