| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
|
FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online October 15, 2001 as doi:10.1096/fj.01-0584fje. |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
,25-Dihydroxyvitamin D3 modulates human adipocyte metabolism via nongenomic action 1
University of Tennessee, Knoxville, Tennessee 37996, USA;
* University of California, Riverside, California 92521, USA; and
Zen-Bio, Research Triangle Park, North Carolina 27709, USA
2Correspondence: University of Tennessee, 1215 W. Cumberland Ave., #229, Knoxville, TN 37996-1900, USA. E-mail: mzemel{at}utk.edu
SPECIFIC AIM
The present study was designed to determine the direct role of 1
,25-dihyroxyvitamin D3 (1,25-(OH)2-D3) in modulating adipocyte Ca2+ signaling and lipid metabolism via nongenomic action.
PRINCIPAL FINDINGS
1. 1,25-(OH)2-D3 stimulates Ca2+ influx in human adipocytes
1,25-(OH)2-D3 induced a significant increase of [Ca2+]i in human adipocytes in a dose-dependent manner, with 13.33 ± 1.22 nM vs. 23.33 ± 2.81 nM increases over baseline (5 nM vs.10 nM 1,25-(OH)2-D3 treatment, P < 0.02) (Fig. 1
upper left), respectively. This action was mimicked by 1,25-dihydroxylumisterol3 (1,25-(OH)2-lumisterol3), a specific agonist for membrane vitamin D receptor (mVDR). 1,25-(OH)2-lumisterol3 caused marked dose-responsive increases in human adipocyte [Ca2+]i, with 27.75 ± 7.82 nM and 131.00 ± 11.00 nM increases over baseline (P<0.001), respectively (Fig. 1
, upper right), whereas these effects were completely prevented by pretreatment of human adipocytes with 1ß,25-dihydroxyvitamin D3 (1ß,25-(OH)2-D3), a specific antagonist for mVDR (Fig. 1
, lower panel).
|
2. 1,25-(OH)2-D3 stimulates lipogenesis and inhibits lipolysis in human adipocytes
1,25-(OH)2-D3 (5 nM) caused a 40% increase in adipocyte fatty acid synthase (FAS) activity over 48 h (P<0.05) whereas 1,25-(OH)2-lumisterol3 exerted a more potent effect, with a 2.5-fold increase in FAS activity (P<0.001, Fig. 2
, lower panel). However, pretreatment of humanadipocytes with 1ß,25-(OH)2-D3 completely prevented this stimulation of FAS (Fig. 2
, lower panel). A similar stimulation of FAS mRNA expression was also observed, with 2- and 2.5-fold increases on 1,25-(OH)2-D3 and 1,25-(OH)2-lumisterol3 treatment (P<0.001), respectively, whereas this stimulation was completely blocked by 1ß,25-(OH)2-D3 (Fig. 2
, upper panel). Consistent with this, 1,25-(OH)2-D3 (5 nM) stimulated a 50% increase in glycerol-3-phosphate dehydrogenase (GPDH) activity (P<0.05); a markedly greater stimulation of 2.8-fold was found with 1,25-(OH)2-lumisterol3 treatment (P<0.001). Although 1ß,25-(OH)2-D3 exerted little effect on 1,25-(OH)2-D3-stimulated GPDH activity, it markedly inhibited 1,25-(OH)2-lumisterol3-stimulated GPDH activity.
|
1,25-(OH)2-D3 exerted a inhibitory effect on adipocyte basal lipolysis, with a 35% reduction (P<0.05). Inhibition of 50% was found with 1,25-(OH)2-lumisterol3 treatment (P<0.01). Conversely, this inhibition was completely prevented by pretreatment with 1ß,25-(OH)2-D3. Treatment of human adipocytes with isoproterenol resulted in a 3.2-fold increase in lipolysis (P<0.001), whereas 1,25-(OH)2-D3 and 1,25-(OH)2-lumisterol3 inhibited isoproterenol-stimulated lipolysis by 56% and 53% (P<0.001), respectively. Pretreatment with 1ß,25-(OH)2-D3 prevented this inhibitory effect of 1,25-(OH)2-D3 and 1,25-(OH)2-lumisterol3 on isoproterenol-stimulated lipolysis.
CONCLUSION
Intracellular Ca2+ ([Ca2+]i) plays a key role in metabolic disorders associated with obesity and insulin resistance (123). We previously reported that increasing [Ca2+]i via stimulation of either receptor or voltage-mediated calcium channels stimulates the expression and activity of FAS, a key enzyme in de novo lipogenesis, and inhibits basal and agonist-stimulated lipolysis in both human and murine adipocytes. Increasing [Ca2+]i appears to promote triglyceride accumulation in adipocytes by exerting a coordinated control over lipogenesis and lipolysis. Therefore, identifying and characterizing hormones that modulate [Ca2+]i is a logical approach for elucidating novel mechanisms involved in modulating adiposity.
Data presented here show that the calcitropic hormone 1,25-(OH)2-D3 exhibits a role in modulating adipocyte Ca2+ signaling, resulting in a coordinated control over lipogenesis and lipolysis. These data indicate that 1,25-(OH)2-D3 plays a novel role in mediating energy homeostasis in adipose tissue and suggest that the 1,25-(OH)2-D3-mediated signaling pathways in regulating adipocyte energy metabolism may represent a suitable target for the development of pharmacological and/or nutritional interventions in obesity. Although it is possible that 1,25-(OH)2-D3 may also exert its effects on adipocyte lipid metabolism via other signal transduction pathways, this is unlikely, as we have previously demonstrated similar effects that result from direct activation of adipocyte Ca2+ channels that can be reversed by Ca2+ channel inhibition. Moreover, we recently demonstrated that protein kinase C does not mediate [Ca2+]i inhibition of lipolysis.
1,25-(OH)2-D3, the biologically active form of the vitamin D, was originally believed to function solely via a nuclear receptor, nVDR. However, this concept was challenged by recent studies demonstrating that 1,25-(OH)2-D3 is able to induce rapid nongenomic effects in nVDR null cells or cells from nVDR knockout mice, indicating that the genomic model of 1,25-(OH)2-D3 action is not complete. 1,25-(OH)2-D3 also generates rapid, nongenomic signal transduction, including stimulation of Ca2+ influx via a putative mVDR in a wide variety of cells. Nemere et al. identified a membrane-associated protein with a high binding affinity for 1,25-(OH)2-D3 that mediated the rapid nongenomic regulation of calcium transport and protein kinase C.
The analogs of 1,25-(OH)2-D3 have been examined extensively in terms of their ability to generate genomic or non genomic biological response. Several reports demonstrated that 6-s-cis-locked analogs of 1,25-(OH)2-D3 (such as 1,25-dihydroxylumisterol3) are specific for nongenomic action, including stimulation of Ca2+ influx, via binding to mVDR. In contrast, this analog exhibits low binding affinity to nVDR and fails to activate the genomic pathway. Further, 1ß,25-dihyroxyvitamin D3 blocks rapid physiological response elicited by 1,25-(OH)2-D3 or 1,25-dihydroxylumisterol3 but has no effect on nVDR. Therefore, 1,25-dihydroxylumisterol3 is a specific agonist of nongenomic action and 1ß,25-dihyroxyvitamin D3 is a specific antagonist of nongenomic action.
It is noteworthy that we found 1,25-dihydroxylumisterol3 to exert more potent effects in modulating adipocyte [Ca2+]i and lipid metabolism and that 1ß,25-dihyroxyvitamin D3 completely blocked these effects. This suggests that 1,25-dihydroxylumisterol3 acts on the mVDR solely to generate nongenomic action in adipocytes whereas 1,25-(OH)2-D3 may target both mVDR and nVDR to mediate nongenomic and genomic actions, which may interact with each other, thereby compromising the modulation of lipid metabolism. These data demonstrate that 1,25-(OH)2-D3-mediated nongenomic action via mVDR may play a major role in regulating adipocyte lipogenesis and lipolysis.
Regulation of adipocyte metabolism via 1,25-(OH)2-D3 signaling pathways may play an important role in the development of obesity in vivo. Several lines of evidence demonstrate that the circulating 1,25-(OH)2-D3 level is elevated in obese humans. Accordingly, the 1,25-(OH)2-D3-mediated signaling pathway in regulating adipocyte energy homeostasis may represent a suitable target for the development of pharmacological and/or nutritional interventions in obesity. Previous studies showed that increasing dietary calcium suppressed 1,25-(OH)2-D3 levels. Accordingly, we tested the hypothesis that dietary calcium suppression of 1,25-(OH)2-D3 would reduce adipocyte [Ca2+]i and thereby inhibit triglyceride accumulation by coordinated control over lipogenesis and lipolysis. Our data demonstrated that suppression of 1,25-(OH)2-D3 by increasing dietary calcium decreased adipocyte intracellular Ca2+, stimulated lipolysis, inhibited lipogenesis, and increased adipocyte uncoupling protein 2 (UCP2) expression and core temperature in aP2-agouti transgenic mice; dietary calcium not only attenuated diet-induced obesity but also accelerated weight loss and fat mass reduction secondary to caloric restriction. These results have been supported by recent clinical observations.
In summary, these data suggest that 1,25-(OH)2-D3 modulates adipocyte Ca2+ signaling and, consequently, exerts a coordinated control over lipogenesis and lipolysis. Thus, a direct inhibition of 1,25-(OH)2-D3-induced [Ca2+]i may contribute to an anti-obesity effect of dietary calcium, and the mVDR-mediated nongenomic pathway may represent an important target for development of therapeutic interventions in obesity.
|
FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.01-0584fje; to cite this article, use FASEB J. (October 15, 2001) 10.1096/fj.01-0584fje 
This article has been cited by other articles:
|
|
 |
|
  J. A. Yanovski, S. J. Parikh, L. B. Yanoff, B. I. Denkinger, K. A. Calis, J. C. Reynolds, N. G. Sebring, and T. McHugh Effects of Calcium Supplementation on Body Weight and Adiposity in Overweight and Obese Adults: A Randomized Trial Ann Intern Med, June 16, 2009; 150(12): 821 - 829. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. T. Mizwicki and A. W. Norman The Vitamin D Sterol-Vitamin D Receptor Ensemble Model Offers Unique Insights into Both Genomic and Rapid-Response Signaling Sci. Signal., June 16, 2009; 2(75): re4 - re4. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Van Loan The Role of Dairy Foods and Dietary Calcium in Weight Management J. Am. Coll. Nutr., February 1, 2009; 28(Supplement_1): 120S - 129S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Sneve, Y Figenschau, and R Jorde Supplementation with cholecalciferol does not result in weight reduction in overweight and obese subjects Eur. J. Endocrinol., December 1, 2008; 159(6): 675 - 684. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kong and Y. C. Li Molecular mechanism of 1,25-dihydroxyvitamin D3 inhibition of adipogenesis in 3T3-L1 cells Am J Physiol Endocrinol Metab, May 1, 2006; 290(5): E916 - E924. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. P. Heaney Nutrition and Chronic Disease Mayo Clin. Proc., March 1, 2006; 81(3): 297 - 299. [Full Text] [PDF]
|
|
|
|
 |
|
 N. Boon, G. B. Hul, N. Viguerie, A. Sicard, D. Langin, and W. H. Saris Effects of 3 diets with various calcium contents on 24-h energy expenditure, fat oxidation, and adipose tissue message RNA expression of lipid metabolism-related proteins Am. J. Clinical Nutrition, December 1, 2005; 82(6): 1244 - 1252. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Boon, L. L. J. Koppes, W. H. M. Saris, and W. Van Mechelen The Relation between Calcium Intake and Body Composition in a Dutch Population: The Amsterdam Growth and Health Longitudinal Study Am. J. Epidemiol., July 1, 2005; 162(1): 27 - 32. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Sun and M. B. Zemel Calcium and Dairy Products Inhibit Weight and Fat Regain during Ad Libitum Consumption Following Energy Restriction in Ap2-Agouti Transgenic Mice J. Nutr., November 1, 2004; 134(11): 3054 - 3060. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Parikh, M. Edelman, G. I. Uwaifo, R. J. Freedman, M. Semega-Janneh, J. Reynolds, and J. A. Yanovski The Relationship between Obesity and Serum 1,25-Dihydroxy Vitamin D Concentrations in Healthy Adults J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1196 - 1199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Shapses, S. Heshka, and S. B. Heymsfield Effect of Calcium Supplementation on Weight and Fat Loss in Women J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 632 - 637. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J Parikh and J. A Yanovski Calcium intake and adiposity Am. J. Clinical Nutrition, February 1, 2003; 77(2): 281 - 287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Zemel Mechanisms of Dairy Modulation of Adiposity J. Nutr., January 1, 2003; 133(1): 252S - 256. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Zemel Regulation of Adiposity and Obesity Risk By Dietary Calcium: Mechanisms and Implications J. Am. Coll. Nutr., April 1, 2002; 21(2): 146S - 151. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
