Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Ver. Summary Created by Modification Content Size Created at Operation
1 + 2336 word(s) 2336 2021-07-09 12:19:48 |
2 format correct Meta information modification 2336 2021-08-02 14:27:42 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Takaya, J. Pregnancy Calcium-Deficiency, Offspring Insulin Resistance. Encyclopedia. Available online: (accessed on 11 December 2023).
Takaya J. Pregnancy Calcium-Deficiency, Offspring Insulin Resistance. Encyclopedia. Available at: Accessed December 11, 2023.
Takaya, Junji. "Pregnancy Calcium-Deficiency, Offspring Insulin Resistance" Encyclopedia, (accessed December 11, 2023).
Takaya, J.(2021, July 30). Pregnancy Calcium-Deficiency, Offspring Insulin Resistance. In Encyclopedia.
Takaya, Junji. "Pregnancy Calcium-Deficiency, Offspring Insulin Resistance." Encyclopedia. Web. 30 July, 2021.
Pregnancy Calcium-Deficiency, Offspring Insulin Resistance

Adverse nutritional conditions during pregnancy may permanently alter the structure or function of specific organs in the offspring, leading to various chronic diseases in adulthood. Maternal undernutrition, and the consequent low birth weight of offspring, predisposes the offspring to various diseases, including adult-onset insulin resistance syndrome. Calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome. Cortisol, the most important glucocorticoid, is considered to lead to insulin resistance and metabolic syndrome. 11β-hydroxysteroid dehydrogenase-1 is a key enzyme that catalyzes the intracellular conversion of cortisone to physiologically active cortisol. 

calcium insulin resistance pregnancy 11β-hydroxysteroid dehydrogenase-1

1. Calcium and Insulin Resistance

Ca is an important second messenger in signal transduction pathways that regulate a wide variety of processes, including gene expression, protein synthesis, secretion, muscle contraction, metabolism, and apoptosis [1]. A link between Ca intake and insulin resistance in obesity and metabolic syndrome has been identified in epidemiological studies [2][3]. Several observational prospective studies have also shown a relationship between low or insufficient oral Ca intake and the incidence of type 2 diabetes mellitus (DM2) [4][5] and metabolic syndrome [6]. It was shown that individuals who have poor Ca intake present higher body weight [7]. Furthermore, a Ca-rich diet is known to improve insulin sensitivity [8][9]. A systematic review of randomized clinical trials suggested that Ca supplementation induces a small, but statistically significant, weight loss in overweight and obese individuals [10]. Earlier dose-dependent meta-analyses of cohort studies have shown that dietary intake of Ca prevents the development of DM2 [11][12]. Recently Wu et al. reported that in the large prospective cohort study, higher serum Ca levels precede peripheral insulin resistance, and this relation plays a role in the development of hypertension [13].

However, the mechanisms underlying this relationship remain poorly understood. Dietary Ca appears to play a pivotal role in the regulation of energy metabolism and obesity risk. Ca has the ability to modulate energy metabolism through calciotropic hormone concentrations: calcitriol and parathyroid hormone (PTH) [7]. A high-Ca diet is known to attenuate body fat accumulation and weight gain during periods of overconsumption of an energy-dense diet and promote fat breakdown and preserve metabolism during periods of caloric restriction, thereby markedly accelerating the loss of weight and fat [14]. Thus, a diet that is poor in Ca could inhibit lipolysis, stimulate lipogenesis, and decrease lipid oxidation [15]. Severe Ca deficiency increases visceral fat accumulation, down-regulating genes associated with fat oxidation, and increases insulin resistance while elevating serum PTH in estrogen-deficient rats [16]. The specific roles of Ca signaling and endoplasmic reticulum stress affect the development of insulin resistance and atherosclerosis [17].

Vitamin D plays a major role in Ca ion homeostasis by regulating Ca transport and bone mineralization. Vitamin D deficiency is associated with direct effects on offspring health such as low birth weight, poor skeletal health, obesity, and insulin resistance [18][19]. Similarly, prenatal vitamin D deficiency is associated with increased insulin resistance and inflammatory mediators in childhood [20][21]. A study of rats revealed that offspring who were born from mothers under vitamin D deficiency had increased fatty acid and markers of inflammation and oxidative stress in the liver and higher prevalence of liver steatosis [22]. In a mouse study, maternal vitamin D deficiency induced structural remodeling of the pancreas and impaired insulin secretion due to reduced gene expression of PDX-1, which regulates the expression of GLUT2, glucokinase, and insulin in adult offspring [19]. Maternal Vitamin D deficiency in a large birth cohort involving Indian children predicted higher insulin resistance at 9.5 years old [18].

2. Calcium and Epigenetics

The effects of the nutritional status of the mother have been discussed for many years, and several studies have considered the nutritional status of the mother during pregnancy as an environmental epigenetic factor that may play an important role in fetal development [23]. Regulatory regions of the genome can be modified through epigenetic processes during prenatal life. The modification of chromatin and DNA contributes to a large well-documented process known as “programming”. Programming of fetal insulin resistance was reported to be induced by intrauterine abnormal activation of inflammation, adipokines, and the endoplasmic reticulum stress [24]. The correlation between gut dysbiosis and metabolic disturbance has attracted attention. Li et al. reported that imbalance in maternal Ca intake promotes body weight gain in offspring, which may be mediated by calcium’s modulation on the gut microbiota and lipid metabolism [25].

Epigenetics is the study of mitotically heritable alterations in gene expression potential that are not caused by changes in DNA sequences [26]. Epigenetic mechanisms, which are established during prenatal and early postnatal development, function throughout the lifetime of complex organisms to maintain the diverse gene expression patterns of different cell types. Several molecular mechanisms, including the methylation of cytosines within CpG dinucleotides, various modifications of the histone proteins that package DNA in the nucleus, and cell-autonomous expression of a myriad of auto-regulatory DNA-binding proteins, interact to perpetuate the regional chromatin conformation that dictates which genes will be transcriptionally competent in specific cell types [27]. Ca has been indirectly associated with epigenetic modifications [28]. Conjugated linoleic acid and Ca supplementation modified the methylation pattern of fatty-acid-related genes under a high-fat diet in adult mice [29].

3. 11β-Hydroxysteroid Dehydrogenase

3.1. Glucocorticoid and 11β-Hydroxysteroid Dehydrogenase-1

Preliminary data suggest that circulating cortisol concentrations are higher in patients with metabolic syndrome compared to healthy subjects [30][31][32]. Dysregulation of glucocorticoid action has been proposed to be one of the central features of metabolic syndrome [33]. In the major metabolic organs, tissue sensitivity and exposure to glucocorticoids are determined by the levels of intracellular peroxisome proliferator-activated receptor α (PPARα), glucocorticoid receptor (GR), and the activity of the microsomal enzyme 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1). 11β-HSD1 converts inactive glucocorticoids (cortisone in humans and 11-dehydrocorticosterone in rodents) to their active forms (cortisol and corticosterone, respectively) [34]. 11β-HSD1 is highly expressed in liver and adipose tissue, where glucocorticoids reduce insulin sensitivity and action [34][35][36]. The activity of 11β-HSD1 in liver and adipose tissue might contribute to the development of several features of insulin resistance or metabolic syndrome [37][38][39]. Obese individuals have increased 11β-HSD1 mRNA in both subcutaneous and visceral fat tissue [40]. Experimental studies have shown higher 11β-HSD1 expression in adipose tissue associated with features of metabolic syndrome such as increased waist circumference and insulin resistance [41].

Harno et al. reported that liver-specific 11β-HSD1 knockout mice given low-dose 11-dehydrocorticosterone do not show any of the adverse metabolic effects seen in wild-type mice [42]. This result implies that liver-derived intra-tissue glucocorticoids, rather than circulating glucocorticoids, contribute to the development of metabolic syndrome and suggest that local action within hepatic tissue mediates these effects. In contrast, Morgan et al. reported that adipose-specific 11β-HSD1 knockout mice given higher dose glucocorticoids are protected from hepatic steatosis and circulating fatty acid excess, whereas liver-specific 11β-HSD1 knockout mice develop full metabolic syndrome phenotypes [43]. This result demonstrates that 11β-HSD1, particularly in adipose tissue, is key to the development of the adverse metabolic profile associated with circulating glucocorticoid excess.

11β-hydroxysteroid dehydrogenase-2 (11β-HSD2) converts excess cortisol into inactive cortisone [44]. Phosphoenolpyruvate carboxykinase (PEPCK), a key hepatic gluconeogenic enzyme, simultaneously decarboxylates and phosphorylates oxaloacetate into phosphoenolpyruvate in one of the earliest rate-limiting steps of gluconeogenesis. 11β-HSD1 regulates key hepatic gluconeogenic enzymes, including PEPCK, through the amplification of GR-mediated tissue glucocorticoid action [34][36][44].

3.2. A Calcium-Deficient Diet Affects Hepatic 11β-Hydroxysteroid Dehydrogenase-1 Expression in the Liver of Dams

We previously reported that after 2 weeks of the low-Ca diet (low-Ca group: 0.008% Ca) or control diet (control group: 0.90% Ca), no differences in serum glucose, corticosterone, or insulin levels were observed between the two groups. In adulthood, 1 rat month is comparable to 3 human years [30]. The homeostasis model assessment of insulin resistance (HOMA-IR) has proved to be a robust tool for the assessment of insulin resistance [45]. The low-Ca group rats showed higher values of HOMA-IR (p < 0.05) and intact parathyroid hormone (p < 0.05) and lower values of adiponectin (p < 0.01). In the low-Ca group, the expression of hepatic Hsd11b1 mRNA was up-regulated, and hepatic Pck1 expression was down-regulated (p < 0.001). The expression levels of Nr3c1Ppara, and Hsd11b2 showed a similar tendency. The 2-week Ca-deficient diet in rats was associated with the upregulation of the hepatic expression of Hsd11b1 mRNA, which occurred before the animals developed obesity or overt features of metabolic syndrome [46]. Over-activity of 11β-HSD1 is associated with increased intracellular active glucocorticoids [34][35][36]. Rodent genetic studies have suggested that increased Hsd11b1 expression or activity increases the risk of several components of metabolic syndrome [37][38]. In summary, a low-Ca diet alters glucocorticoid metabolism, which leads to hepatic upregulation of Hsd11b1, and is possibly a key mechanism of the induction of metabolic complications caused by Ca deficiency [46].

4. A Ca-Deficient Diet in Pregnant or Nursing Rats Affects the Offspring

Lillycrop et al. reported that pregnant rats on a protein-restricted diet developed hypomethylation and increased expression from the Ppara and Nr3c1 promoters in the liver of the offspring [47][48]. This demonstrates that maternal nutrition during pregnancy can affect the regulation of non-imprinted genes via the altered epigenetic regulation of gene expression, thereby inducing different metabolic phenotypes. A high-fat diet during pregnancy was reported to induce neonatal gender-specific hepatic fat accumulation by increased pck1 expression and histone modification [49].

4.1. The Methylation of Specific Cytosines within the 11β-Hydroxysteroid Dehydrogenase-1 Promoter in the Liver of the Offspring

We investigated the methylation of individual CpG dinucleotides in glucocorticoid-related genes in liver tissue of neonatal offspring from Ca-deficient rat dams. Female rats consumed either a Ca-deficient (0.008% Ca) or control (0.90% Ca) diet ad libitum from 3 weeks before conception to 21 days after parturition. Pups were allowed to nurse from their original mothers and were then sacrificed on day 21. The methylation of CpG dinucleotides in the Pck1 [50]Ppara, Nr3c1Hsd11b1, and Hsd11b2 promoters was measured in liver tissue by pyrosequencing [42]. The methylation levels of all genes did not differ between groups, except for Hsd11b1, which was significantly lower in the rats from the Ca-deficient dams (p < 0.05). Serum corticosterone levels were higher in the male pups from the Ca-deficient dams than in those from the control dams (p < 0.05). The expression levels of Pck1 and Nr3c1 were significantly lower in the Ca-deficient group than in the control group, whereas those of Hsd11b1, Hsd11b2, and Ppara did not differ significantly [51].

Although the hepatic expression of Hsd11b1 may have been initially up-regulated by epigenetic mechanisms in the offspring from Ca-deficient dams, Hsd11b1 was likely down-regulated by other mechanisms during the early postnatal period. The methylation level of hepatic Hsd11b1 was altered in the offspring as a consequence of the maternal dietary manipulation, but the epigenetic changes were not reflected in corresponding alterations in transcription. The nuclear receptor co-repressor complex is affected by environmental factors such as nutrients and hormones, which can lead to altered DNA methylation, acetylation, histone modification, other epigenetic changes, or some combination thereof; such epigenetic changes can and do alter the activity of DNA. These factors can also alter feedback loops involving nuclear receptors that normally regulate repression and maintain balance [52].

The down-regulation of Hsd11b1 suggests that a compensatory mechanism may diminish cortisol production in the liver. Reduced hepatic glucocorticoid exposure also represents a compensatory mechanism that limits the metabolic complications of insulin resistance. In our study, no significant difference in serum 11β-HSD1 levels was found among the offspring groups; however, this may have been due to tissue-specific differences between serum and liver. Whether glucocorticoids modulate Hsd11b1 expression is unknown, and Hsd11b1 expression differs greatly between the liver and other tissues [53][54][55]. Obese rodents exhibit tissue-specific dysregulation of 11β-HSD1; it is usually up-regulated in adipose tissue and down-regulated in the liver [56][57]. In both obese Zucker rats and obese humans, 11β-HSD1 activity is high in adipose tissue but low in the liver [54][55][58]. In adipose tissue and smooth muscle cells, glucocorticoid induces Hsd11b1 mRNA expression, but contradictory results have been obtained in the liver [55][58].

In summary, a Ca-deficient diet during pregnancy and nursing induced hypomethylation of specific CpG dinucleotides in the Hsd11b1 promoter in the liver tissue of neonatal offspring. These changes in Hsd11b1 expression likely contribute to marked increases in glucocorticoid hormone action in liver tissue [44] and potentiate the induction of insulin resistance during adult life [33].

4.2. A Ca-Deficient Diet in Dams during Gestation Increases Insulin Resistance in Male Offspring

The offspring rats of the same experimental methods as described in the previous section were raised to adults. Pups were allowed to nurse from their original mothers until weaning, when they were fed a control diet. The offspring were then sacrificed at an age of 180 days. The mean levels of insulin and glucose as well as the HOMA-IR values were higher only in the male offspring from the Ca-deficient dams than in those from the control dams (p < 0.01) [59]. In all offspring, the serum leptin levels were correlated with the serum insulin levels, and they were inversely correlated with the levels of ionized Ca.

A Ca-deficient diet in dams during gestation and early nursing may alter the glucocorticoid metabolism of her offspring, resulting in higher intracellular glucocorticoid concentration in the hepatic cells of the offspring; this abnormal glucocorticoid metabolism may induce the metabolic complications associated with Ca deficiency. Dietary Ca restriction in dams during pregnancy alters postnatal growth, the expression of Hsd11b1, and insulin resistance in a sex-specific manner.

4.3. Osteocalcin in the Offspring from a Ca-Deficient Dams

Osteocalcin (OC), or bone γ carboxyglutamic acid (Gla) protein, is the most abundant non-collagenous bone matrix protein [60]. OC is specifically expressed in osteoblast lineage cells and secreted from bone into the bloodstream [61]. OC is subjected to post-translational carboxylation by a vitamin K-dependent carboxylase to yield carboxylated (Gla-OC) and undercarboxylated (Glu-OC) molecules [62]. Glu-OC acts directly on pancreatic β-cells to increase insulin secretion, as well as insulin sensitivity and glucose tolerance [63][64][65]. The offspring rats of the same experimental methods as described in the previous section were raised to adults [59]. The mean levels of Glu-OC in Ca-deficient female offspring were higher than those in control female offspring and control male offspring. The mean levels of Gla-OC were higher in Ca-deficient female offspring than those in control female offspring, whereas no significant difference was observed in these measures between the two groups in male offspring. The effects of Glu-OC on glucose homeostasis have been reported to differ by sex [66]. Increased Glu-OC could contribute to lower insulin resistance in female Ca-deficient offspring, and therefore might be beneficial for glucose metabolism. Consequently, only male Ca-deficient offspring may acquire insulin resistance.


  1. Berridge, M.J.; Bootman, M.D.; Roderick, H.L. Calcium signalling: Dynamics, homeostasis and remodelling. Nat. Rev. Mol. Cell Biol. 2003, 4, 517–529.
  2. Pikilidou, M.I.; Lasaridis, A.N.; Sarafidis, P.A.; Befani, C.D.; Koliakos, G.G.; Tziolas, I.M.; Kazakos, K.A.; Yovos, J.G.; Nilsson, P.M. Insulin sensitivity increase after calcium supplementation and change in intraplatelet calcium and sodium-hydrogen exchange in hypertensive patients with Type 2 diabetes. Diabet. Med. 2009, 26, 211–219.
  3. Schrager, S. Dietary calcium intake and obesity. J. Am. Board Fam. Pract. 2005, 18, 205–210.
  4. Liu, S.; Song, Y.; Ford, E.S.; Manson, J.E.; Buring, J.E.; Ridker, P.M. Dietary calcium, vitamin D, and the prevalence of metabolic syndrome in middle-aged and older U.S. women. Diabetes Care 2005, 28, 2926–2932.
  5. Pittas, A.G.; Lau, J.; Hu, F.B.; Dawson-Hughes, B. The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 2007, 92, 2017–2029.
  6. Pereira, M.A.; Jacobs, D.R., Jr.; Van Horn, L.; Slattery, M.L.; Kartashov, A.I.; Ludwig, D.S. Dairy consumption, obesity, and the insulin resistance syndrome in young adults: The CARDIA Study. JAMA 2002, 287, 2081–2089.
  7. Zemel, M.B. Regulation of adiposity and obesity risk by dietary calcium: Mechanisms and implications. J. Am. Coll. Nutr. 2002, 21, 146S–151S.
  8. Ma, B.; Lawson, A.B.; Liese, A.D.; Bell, R.A.; Mayer-Davis, E.J. Dairy, magnesium, and calcium intake in relation to insulin sensitivity: Approaches to modeling a dose-dependent association. Am. J. Epidemiol. 2006, 164, 449–458.
  9. Pittas, A.G.; Harris, S.S.; Stark, P.C.; Dawson-Hughes, B. The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care 2007, 30, 980–986.
  10. Onakpoya, I.J.; Perry, R.; Zhang, J.; Ernst, E. Efficacy of calcium supplementation for management of overweight and obesity: Systematic review of randomized clinical trials. Nutr. Rev. 2011, 69, 335–343.
  11. Aune, D.; Norat, T.; Romundstad, P.R.; Vatten, L.J. Dairy products and the risk of type 2 diabetes: A systematic review and dose-response mata-analysis of cohort studies. Am. J. Clin. Nutr. 2013, 98, 1066–1083.
  12. Gijsbers, L.; Ding, E.L.; Malik, V.S.; De Goede, J.; Geleijnse, J.M.; Soedamah-Muthu, S.S. Consumption of dairy foods and diabetes incidence: A dose-response meta-analysis of observantional studies. Am. J. Clin. Nutr. 2016, 103, 1111–1124.
  13. Wu, X.; Han, T.; Gao, J.; Zhang, Y.; Zhao, S.; Sun, R.; Sun, C.; Niu, Y.; Li, Y. Association of Serum Calcium and Insulin Resistance With Hypertension Risk: A Prospective Population-Based Study. J. Am. Heart Assoc. 2019, 8, e009585.
  14. Zemel, M.B. The role of dairy foods in weight management. J. Am. Coll. Nutr. 2005, 24, 537S–546S.
  15. Xiaoyu, Z.; Payal, B.; Melissa, O.; Zanello, L.P. 1alpha,25(OH)2-vitamin D3 membrane-initiated calcium signaling modulates exocytosis and cell survival. J. Steroid Biochem. Mol. Biol. 2007, 103, 457–461.
  16. Park, S.; Kang, S.; Kim, D.S. Severe calcium deficiency increased visceral fat accumulation, down-regulating genes associated with fat oxidation, and increased insulin resistance while elevating serum parathyroid hormone in estrogen-deficient rats. Nutr. Res. 2020, 73, 48–57.
  17. Ozcan, L.; Tabas, I. Calcium signalling and ER stress in insulin resistance and atherosclerosis. J. Intern. Med. 2016, 280, 457–464.
  18. Krishnaveni, G.V.; Veena, S.R.; Winder, N.R.; Hill, J.C.; Noonan, K.; Boucher, B.J.; Karat, S.C.; Fall, C.H. Maternal vitamin D status during pregnancy and body composition and cardiovascular risk markers in Indian children: The Mysore Parthenon Study. Am. J. Clin. Nutr. 2011, 93, 628–635.
  19. Mala-Ceciliano, T.C.; Barreto-Vianna, A.R.; Brbosa-da-Silva, S.; Aguila, M.B.; Faria, T.S.; Mandarim-de-Lacerda, C.A. Maternal vitamin D-restricted diet has consequences in the formation of pancreatic islet/insulin-signaling in the adult offspring of mice. Endocrine 2016, 54, 60–69.
  20. Ideraabdullah, F.Y.; Belenchia, A.M.; Rosenfeld, C.S.; Kullman, S.W.; Knuth, M.; Mahapatra, D.; Bereman, M.; Levin, E.D.; Peterson, C.A. Maternal vitamin D defciency and developmental origins of health and disease (DOHaD). J. Endocrinol. 2019, 241, 65–80.
  21. Blighe, K.; Chawes, B.L.; Kelly, R.S.; Mirzakhani, H.; McGeachie, M.; Litonjua, A.A.; Weiss, S.T.; Lasky-Su, J.A. Vitamin D prenatal programming of childhood metabolomics profiles at age 3 y. Am. J. Clin. Nutr. 2017, 106, 1092–1099.
  22. Sharma, S.S.; Jangale, N.M.; Harsulkar, A.M.; Gokhale, M.K.; Joshi, B.N. Chronic maternal calcium and 25-hydroxyvitamin deficiency in Wistar rats programs abnormal hepatic gene expression leading to hepatic steatosis in female offspring. J. Nutr. Biochem. 2017, 43, 36–46.
  23. Hsu, C.N.; Tain, Y.L. The Good, the Bad, and the Ugly of Pregnancy Nutrients and Developmental Programming of Adult Disease. Nutrients 2019, 11, 894.
  24. Westermeier, F.; Saez, P.J.; Villalobos-Labra, R.; Sobrevia, L.; Farias-Jofre, M. Programming of fetal insulin resistance in pregnancies with maternal obesity by ER stress and inflammation. Biomed Res. Int. 2014, 2014, 917672.
  25. Li, P.; Tang, T.; Chang, X.; Fan, X.; Chen, X.; Wang, R.; Fan, C.; Qi, K. Abnormality in Maternal Dietary Calcium Intake During Pregnancy and Lactation Promotes Body Weight Gain by Affecting the Gut Microbiota in Mouse Offspring. Mol. Nutr. Food Res. 2019, 63, e1800399.
  26. Jaenisch, R.; Bird, A. Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nat. Genet. 2003, 33, 245–254.
  27. Feinberg, A.P. Phenotypic plasticity and the epigenetics of human disease. Nature 2007, 447, 433–440.
  28. Bocheva, G.; Boyadjieva, N. Epigenetic regulation of fetal bone development and placental transfer of nutrients: Progress for osteoporosis. Interdiscip. Toxicol. 2011, 4, 167–172.
  29. Chaplin, A.; Palou, A.; Serra, F. Methylation analysis in fatty-acid related genes reveals their plasticity associated with conjugated acid and calcium supplementation in adult mice. Eur. J. Nutr. 2017, 56, 879–891.
  30. Sen, Y.; Aygun, D.; Yilmaz, E.; Ayar, A. Children and adolescents with obesity and the metabolic syndrome have high circulating cortisol levels. Neurol. Endocrinol. Lett. 2008, 29, 141–145.
  31. Duclos, M.; Pereira, P.M.; Barat, P.; Gatta, B.; Roger, P. Increased cortisol bioavailability, abdominal obesity, and the metabolic syndrome in obese women. Obes. Res. 2005, 13, 1157–1166.
  32. Weigensberg, M.J.; Toledo-Corral, C.M.; Goran, M.I. Association between the metabolic syndrome and serum cortisol in overweight Latino youth. J. Clin. Endocrinol. Metab. 2008, 93, 1372–1378.
  33. Anagnostis, P.; Athyros, V.G.; Tziomalos, K.; Karagiannis, A.; Mikhailidis, D. The pathogenetic role of cortisol in the metabolic syndrome: A hypothesis. J. Clin. Endocrinol. Metab. 2009, 94, 2692–2701.
  34. Cooper, M.S.; Stewart, P.M. 11β-hydroxysteroid dehydrogenase type 1 and its role in the hypothalamus-pituitary-adrenal axis, metabolic syndrome, and inflammation. J. Clin. Endocrinol. Metab. 2009, 94, 4645–4654.
  35. Walker, B.R. Cortisol—Cause and cure for metabolic syndrome? Diabet. Med. 2006, 23, 1281–1288.
  36. Tomlinson, J.W.; Walker, E.A.; Bujalska, I.J.; Draper, N.; Lavery, G.G.; Cooper, M.S.; Hewison, M.; Stewart, P.M. 11β-hydroxysteroid dehydrogenase type 1: A tissue-specific regulator of glucocorticoid response. Endocr. Rev. 2004, 25, 831–866.
  37. Masuzaki, H.; Yamamoto, H.; Kenyon, C.J.; Elmquist, J.K.; Morton, N.M.; Paterson, J.M.; Shinyama, H.; Sharp, M.G.; Fleming, S.; Mullins, J.J.; et al. Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice. J. Clin. Investig. 2003, 112, 83–90.
  38. Morton, N.M.; Seckl, J.R. 11beta-hydroxysteroid dehydrogenase type 1 and obesity. Front. Horm. Res. 2008, 36, 146–164.
  39. Peng, K.; Pan, Y.; Li, J.; Fan, M.; Yin, H.; Tong, C.; Zhao, Y.; Liang, G.; Zheng, C. 11β-Hydroxysteroid Dehydrogenase Type 1(11β-HSD1) mediates insulin resistance through JNK activation in adipocytes. Sci. Rep. 2016, 6, 37160.
  40. Desbriere, R.; Vuaroqueaux, V.; Achard, V.; Boullu-Ciocca, S.; Labuhn, M.; Dutour, A.; Grino, M. 11beta-hydroxysteroid dehydrogenase type 1 mRNA is increased in both visceral and subcutaneous adipose tissue of obese patients. Obesity 2006, 14, 794–798.
  41. Masuzaki, H.; Paterson, J.; Shinyama, H.; Morton, N.M.; Mullins, J.J.; Seckl, J.R.; Flier, J.S. A transgenic model of visceral obesity and the metabolic syndrome. Science 2001, 294, 2166–2170.
  42. Harno, E.; Cottrell, E.C.; Keevil, B.G.; De Schoolmeester, J.; Bohlooly, Y.M.; Andersen, H.; Turnbull, A.V.; Leighton, B.; White, A. 11-Dehydrocorticosterone causes metabolic syndrome, which is prevented when 11β-HSD1 is knocked out in livers of male mice. Endocrinology 2013, 154, 3599–3609.
  43. Morgan, S.A.; McCabe, E.L.; Gathercole, L.L.; Hassan-Smith, Z.K.; Larner, D.P.; Bujaiska, I.J.; Stewart, P.M.; Tomlinson, J.W.; Lavery, G.G. 11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess. Proc. Natl. Acad. Sci. USA 2014, 111, E2482–E2491.
  44. Draper, N.; Stewart, P.M. 11β-hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action. J. Endocrinol. 2005, 186, 251–271.
  45. Matthews, D.R.; Hosker, J.P.; Rudenski, A.S.; Naylor, B.A.; Treacher, D.F.; Turner, R.C. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985, 28, 412–419.
  46. Takaya, J.; Iharada, A.; Okihana, H.; Kaneko, K. Upregulation of hepatic 11β-hydroxysteroid dehydrogenase-1 expression in calcium-deficient rats. Ann. Nutr. Metab. 2011, 59, 73–78.
  47. Lillycrop, K.A.; Phillips, E.S.; Jackson, A.A.; Hanson, M.A.; Burdge, G.C. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J. Nutr. 2005, 135, 1382–1386.
  48. Lillycrop, K.A.; Phillips, E.S.; Jackson, A.A.; Hanson, M.A.; Burdge, G.C. Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPAR alpha promoter of the offspring. Br. J. Nutr. 2008, 100, 278–282.
  49. Strakovsky, R.S.; Zhang, X.; Zhou, D.; Pan, Y.X. Gestational high fat diet programs hepatic phosphoenolpyruvate carboxykinase gene expression and histone modification in neonatal offspring rats. J. Physiol. 2011, 589, 2707–2717.
  50. Hanson, R.W.; Patel, Y.M. Phosphoenolpyruvate carboxykinase (GTP) gene. Adv. Enzymol. Rel. Areas Mol. Biol. 1994, 69, 203–281.
  51. Takaya, J.; Iharada, A.; Okihana, H.; Kaneko, K. A calcium-deficient diet in pregnant, nursing rats induces hypomethylation of specific cytosines in the 11β-hydroxysteroid dehydrogenase-1 promoter in pup liver. Nutr. Res. 2013, 33, 961–970.
  52. Kaelin, W.G., Jr.; McKnight, S.L. Influence of metabolism on epigenetics and disease. Cell 2013, 153, 56–69.
  53. Lindsay, R.S.; Wake, D.J.; Nair, S.; Bunt, J.; Livingstone, D.E.; Permana, P.A.; Tataranni, P.A.; Walker, B.R. Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pima Indians and Caucasians. J. Clin. Endocrinol. Metab. 2003, 88, 2738–2744.
  54. Paulmyer-Lacrox, O.; Boullu, S.; Oliver, C.; Alessi, M.C.; Grino, M. Expression of the mRNA coding for 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue from obese patients: An in situ hybridization study. J. Clin. Endocrinol. Metab. 2002, 87, 2701–2705.
  55. Rask, E.; Olsson, T.; Sodenberg, S.; Andrew, R.; Livingstone, D.E.; Johnson, O.; Walker, B.R. Tissue-specific dysregulation of cortisol metabolism in human obesity. J. Clin. Endocrinol. Metab. 2001, 86, 1418–1421.
  56. Hemanowski-Vosatka, A.; Balkovec, J.M.; Cheng, K.; Chen, H.Y.; Hernandez, M.; Koo, G.C.; Le Grand, C.B.; Li, Z.; Metzger, J.M.; Mundt, S.S.; et al. 11beta-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J. Exp. Med. 2005, 202, 517–527.
  57. Liu, Y.; Nakagawa, Y.; Wang, Y.; Li, R.; Li, X.; Ohzeki, T.; Friedman, T.C. Leptin activation of corticosterone production in hepatocytes may contribute to the reversal of obesity and hyperglycemia in leptin-deficient ob/ob mice. Diabetes 2003, 52, 1409–1416.
  58. Livingstone, D.E.; Jones, G.C.; Smith, K.; Jamieson, P.M.; Andrew, R.; Kenyon, C.J.; Walker, B.R. Understanding the role of glucocorticoids in obesity: Tissue-specific alterations of corticosterone metabolism in obese Zucker rats. Endocrinology 2001, 141, 560–563.
  59. Takaya, J.; Yamanouchi, S.; Kino, J.; Tanabe, Y.; Kaneko, K. A calcium-deficient diet in dams during gestation increases insulin resistance in male offspring. Nutrients 2018, 10, 1745.
  60. Weinreb, M.; Shinar, D.; Rodan, G.A. Different pattern of alkaline phosphatase, osteopontin, and osteocalcin expression in developing rat bone visualized by in situ hybridization. J. Bone Miner. Res. 1990, 5, 831–842.
  61. Lee, A.J.; Hodges, S.; Eastell, R. Measurement of osteocalcin. Ann. Clin. Biochem. 2000, 37, 432–446.
  62. Hauschka, P.V.; Lian, J.B.; Cole, D.E.; Gundberg, C.M. Osteocalcin and matrix Gla protein: Vitamin K-dependent proteins in bone. Physiol. Rev. 1989, 69, 990–1047.
  63. Ferron, M.; Hinoi, E.; Karsenty, G.; Ducy, P. Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc. Natl. Acad. Sci. USA 2008, 105, 5266–5270.
  64. Ferron, M.; McKee, M.D.; Levine, R.L.; Ducy, P.; Karsenty, G. Intermittent injections of osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice. Bone 2012, 50, 568–575.
  65. Lee, N.K.; Sowa, H.; Hinoi, E.; Ferron, M.; Ahn, J.D.; Confavreux, C.; Dacquin, R.; Mee, P.J.; Mckee, M.D.; Jung, D.Y.; et al. Endocrine regulation of energy metabolism by the skeleton. Cell 2007, 130, 456–469.
  66. Yasutake, Y.; Mizokami, A.; Kawakubo-Yasukochi, T.; Chishaki, S.; Takahashi, I.; Takeuchi, H.; Hirata, M. Long-term oral administration of osteocalcin induces insulin resistance in male mice fed a high-fat, high-sucrose diet. Am. J. Physiol. Endocrinol. Metab. 2016, 310, E662–E675.
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to :
View Times: 264
Revisions: 2 times (View History)
Update Date: 02 Aug 2021