Blueberries improve glucose tolerance without altering body composition in obese postmenopausal mice

Carrie M Elks, Jennifer D Terrebonne, Donald K Ingram, Jacqueline M Stephens, Carrie M Elks, Jennifer D Terrebonne, Donald K Ingram, Jacqueline M Stephens

Abstract

Objective: Metabolic syndrome (MetS) risk increases significantly during menopause and remains elevated postmenopause. Several botanicals, including blueberries (BB), have been shown to delay MetS progression, but few studies have been conducted in postmenopausal animal models. Here, the effects of BB supplementation on obese postmenopausal mice using a chemically induced menopause model were examined.

Methods: After induction of menopause, mice were fed a high-fat diet or the same diet supplemented with 4% BB powder for 12 weeks. Body weight and body composition were measured, and mice were subjected to glucose and insulin tolerance tests. Serum triglycerides and adiponectin were measured, and liver histology and hepatic gene expression were assessed.

Results: Menopausal and BB-supplemented mice had significantly higher body weights and fat mass than control mice, while menopausal mice had impaired glucose tolerance and higher serum triglycerides when compared with control and BB-supplemented mice. Menopausal mice also had hepatic steatosis that was prevented by BB supplementation and correlated with expression of genes involved in hepatic fatty acid oxidation.

Conclusions: BB supplementation prevents the glucose intolerance and hepatic steatosis that occur in obese postmenopausal mice, and these effects are independent of body weight.

Conflict of interest statement

CONFLICTS OF INTEREST STATEMENT

Competing interests: the authors have no competing interests.

© 2015 The Obesity Society.

Figures

Figure 1. Menopause-induced changes in body weight…
Figure 1. Menopause-induced changes in body weight and body composition are not altered by BB supplementation
A) Body weights for all animals throughout study duration. Body weights of VCD-injected mice and BB-supplemented VCD-injected mice were not significantly different from each other, but were significantly different from those of control mice from weeks 8–20 of the study. B) Mean body composition data for various groups at study end (20 weeks). Control mice had significantly less fat mass than V or VB mice, but no changes in fat free mass or fluid were noted. *p

Figure 2. BB supplementation does not improve…

Figure 2. BB supplementation does not improve insulin tolerance, but does improve glucose tolerance, in…

Figure 2. BB supplementation does not improve insulin tolerance, but does improve glucose tolerance, in obese postmenopausal mice
A) Graphical depiction of insulin tolerance time following an i.p. insulin injection. At baseline, V mice had higher blood glucose levels than VB or C groups; however, no changes in blood glucose levels over time were noted among any of the groups in response to an insulin injection. B) Graphical depiction of glucose tolerance over time following an i.p. bolus of glucose. V mice demonstrated impaired glucose tolerance at 30, 45, 60, and 90 minutes post-injection. C) GTT results expressed as area under the curve *p

Figure 3. BB supplementation improves serum triglycerides…

Figure 3. BB supplementation improves serum triglycerides in obese postmenopausal mice

A) Serum triglyceride levels…

Figure 3. BB supplementation improves serum triglycerides in obese postmenopausal mice
A) Serum triglyceride levels at study end. B) Serum adiponectin levels at study end. *p

Figure 4. BB supplementation prevents hepatic steatosis…

Figure 4. BB supplementation prevents hepatic steatosis in obese postmenopausal mice

Representative photomicrographs of H&E-stained…

Figure 4. BB supplementation prevents hepatic steatosis in obese postmenopausal mice
Representative photomicrographs of H&E-stained liver sections at 100x magnifications. Scale bars = 50 um. The livers of V mice (panel B) had more severe lipid deposition than C mice (panel A), and BB supplementation prevented the lipid deposition seen in the menopausal liver (panel C). These qualitative histologic results were verified with a quantitative method for tissue triglyceride measurement; results appear in D. *p

Figure 5. Menopause decreases expression of genes…

Figure 5. Menopause decreases expression of genes associated with hepatic fatty acid oxidation and BB…

Figure 5. Menopause decreases expression of genes associated with hepatic fatty acid oxidation and BB supplementation prevents these changes
Relative expression levels of hepatic A) CD36, B) Cs, and C) Hadha in livers after 12 weeks of HFD or HFD supplemented with BB . **p<0.01, ****p<0.0001 vs. V group. C = cycling HFD control group, V = HFD+VCD, VB = HFD+BB+VCD, Cd36 = fatty acid translocase/CD36, Cs = citrate synthase, and Hadha = long-chain hydroxyacyl-CoA dehydrogenase.
Similar articles
Cited by
References
    1. CDC. Women's Reproductive Health: Menopause. U.S. Department of Health and Human Services; Jul 25, 2012. Available from: http://www.cdc.gov/reproductivehealth/womensrh/menopause.htm.
    1. Carr MC. The Emergence of the Metabolic Syndrome with Menopause. Journal of Clinical Endocrinology & Metabolism. 2003;88:2404–2411. - PubMed
    1. Korytkowski MT, Krug EI, Daly MA, DeRiso L, Wilson JW, Winters SJ. Does androgen excess contribute to the cardiovascular risk profile in postmenopausal women with type 2 diabetes? Metabolism. 2005;54:1626–1631. - PubMed
    1. Romero-Aleshire MJ, Diamond-Stanic MK, Hasty AH, Hoyer PB, Brooks HL. Loss of ovarian function in the VCD mouse-model of menopause leads to insulin resistance and a rapid progression into the metabolic syndrome. Am J Physiol Regul Integr Comp Physiol. 2009;297:R587–R592. - PMC - PubMed
    1. Mayer LP, Devine PJ, Dyer CA, Hoyer PB. The Follicle-Deplete Mouse Ovary Produces Androgen. Biology of Reproduction. 2004;71:130–138. - PubMed
Show all 38 references
Publication types
MeSH terms
Related information
Full text links [x]
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM

NCBI Literature Resources

MeSH PMC Bookshelf Disclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

Follow NCBI
Figure 2. BB supplementation does not improve…
Figure 2. BB supplementation does not improve insulin tolerance, but does improve glucose tolerance, in obese postmenopausal mice
A) Graphical depiction of insulin tolerance time following an i.p. insulin injection. At baseline, V mice had higher blood glucose levels than VB or C groups; however, no changes in blood glucose levels over time were noted among any of the groups in response to an insulin injection. B) Graphical depiction of glucose tolerance over time following an i.p. bolus of glucose. V mice demonstrated impaired glucose tolerance at 30, 45, 60, and 90 minutes post-injection. C) GTT results expressed as area under the curve *p

Figure 3. BB supplementation improves serum triglycerides…

Figure 3. BB supplementation improves serum triglycerides in obese postmenopausal mice

A) Serum triglyceride levels…

Figure 3. BB supplementation improves serum triglycerides in obese postmenopausal mice
A) Serum triglyceride levels at study end. B) Serum adiponectin levels at study end. *p

Figure 4. BB supplementation prevents hepatic steatosis…

Figure 4. BB supplementation prevents hepatic steatosis in obese postmenopausal mice

Representative photomicrographs of H&E-stained…

Figure 4. BB supplementation prevents hepatic steatosis in obese postmenopausal mice
Representative photomicrographs of H&E-stained liver sections at 100x magnifications. Scale bars = 50 um. The livers of V mice (panel B) had more severe lipid deposition than C mice (panel A), and BB supplementation prevented the lipid deposition seen in the menopausal liver (panel C). These qualitative histologic results were verified with a quantitative method for tissue triglyceride measurement; results appear in D. *p

Figure 5. Menopause decreases expression of genes…

Figure 5. Menopause decreases expression of genes associated with hepatic fatty acid oxidation and BB…

Figure 5. Menopause decreases expression of genes associated with hepatic fatty acid oxidation and BB supplementation prevents these changes
Relative expression levels of hepatic A) CD36, B) Cs, and C) Hadha in livers after 12 weeks of HFD or HFD supplemented with BB . **p<0.01, ****p<0.0001 vs. V group. C = cycling HFD control group, V = HFD+VCD, VB = HFD+BB+VCD, Cd36 = fatty acid translocase/CD36, Cs = citrate synthase, and Hadha = long-chain hydroxyacyl-CoA dehydrogenase.
Similar articles
Cited by
References
    1. CDC. Women's Reproductive Health: Menopause. U.S. Department of Health and Human Services; Jul 25, 2012. Available from: http://www.cdc.gov/reproductivehealth/womensrh/menopause.htm.
    1. Carr MC. The Emergence of the Metabolic Syndrome with Menopause. Journal of Clinical Endocrinology & Metabolism. 2003;88:2404–2411. - PubMed
    1. Korytkowski MT, Krug EI, Daly MA, DeRiso L, Wilson JW, Winters SJ. Does androgen excess contribute to the cardiovascular risk profile in postmenopausal women with type 2 diabetes? Metabolism. 2005;54:1626–1631. - PubMed
    1. Romero-Aleshire MJ, Diamond-Stanic MK, Hasty AH, Hoyer PB, Brooks HL. Loss of ovarian function in the VCD mouse-model of menopause leads to insulin resistance and a rapid progression into the metabolic syndrome. Am J Physiol Regul Integr Comp Physiol. 2009;297:R587–R592. - PMC - PubMed
    1. Mayer LP, Devine PJ, Dyer CA, Hoyer PB. The Follicle-Deplete Mouse Ovary Produces Androgen. Biology of Reproduction. 2004;71:130–138. - PubMed
Show all 38 references
Publication types
MeSH terms
Related information
Full text links [x]
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM

NCBI Literature Resources

MeSH PMC Bookshelf Disclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

Follow NCBI
Figure 3. BB supplementation improves serum triglycerides…
Figure 3. BB supplementation improves serum triglycerides in obese postmenopausal mice
A) Serum triglyceride levels at study end. B) Serum adiponectin levels at study end. *p

Figure 4. BB supplementation prevents hepatic steatosis…

Figure 4. BB supplementation prevents hepatic steatosis in obese postmenopausal mice

Representative photomicrographs of H&E-stained…

Figure 4. BB supplementation prevents hepatic steatosis in obese postmenopausal mice
Representative photomicrographs of H&E-stained liver sections at 100x magnifications. Scale bars = 50 um. The livers of V mice (panel B) had more severe lipid deposition than C mice (panel A), and BB supplementation prevented the lipid deposition seen in the menopausal liver (panel C). These qualitative histologic results were verified with a quantitative method for tissue triglyceride measurement; results appear in D. *p

Figure 5. Menopause decreases expression of genes…

Figure 5. Menopause decreases expression of genes associated with hepatic fatty acid oxidation and BB…

Figure 5. Menopause decreases expression of genes associated with hepatic fatty acid oxidation and BB supplementation prevents these changes
Relative expression levels of hepatic A) CD36, B) Cs, and C) Hadha in livers after 12 weeks of HFD or HFD supplemented with BB . **p<0.01, ****p<0.0001 vs. V group. C = cycling HFD control group, V = HFD+VCD, VB = HFD+BB+VCD, Cd36 = fatty acid translocase/CD36, Cs = citrate synthase, and Hadha = long-chain hydroxyacyl-CoA dehydrogenase.
Similar articles
Cited by
References
    1. CDC. Women's Reproductive Health: Menopause. U.S. Department of Health and Human Services; Jul 25, 2012. Available from: http://www.cdc.gov/reproductivehealth/womensrh/menopause.htm.
    1. Carr MC. The Emergence of the Metabolic Syndrome with Menopause. Journal of Clinical Endocrinology & Metabolism. 2003;88:2404–2411. - PubMed
    1. Korytkowski MT, Krug EI, Daly MA, DeRiso L, Wilson JW, Winters SJ. Does androgen excess contribute to the cardiovascular risk profile in postmenopausal women with type 2 diabetes? Metabolism. 2005;54:1626–1631. - PubMed
    1. Romero-Aleshire MJ, Diamond-Stanic MK, Hasty AH, Hoyer PB, Brooks HL. Loss of ovarian function in the VCD mouse-model of menopause leads to insulin resistance and a rapid progression into the metabolic syndrome. Am J Physiol Regul Integr Comp Physiol. 2009;297:R587–R592. - PMC - PubMed
    1. Mayer LP, Devine PJ, Dyer CA, Hoyer PB. The Follicle-Deplete Mouse Ovary Produces Androgen. Biology of Reproduction. 2004;71:130–138. - PubMed
Show all 38 references
Publication types
MeSH terms
Related information
Full text links [x]
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Figure 4. BB supplementation prevents hepatic steatosis…
Figure 4. BB supplementation prevents hepatic steatosis in obese postmenopausal mice
Representative photomicrographs of H&E-stained liver sections at 100x magnifications. Scale bars = 50 um. The livers of V mice (panel B) had more severe lipid deposition than C mice (panel A), and BB supplementation prevented the lipid deposition seen in the menopausal liver (panel C). These qualitative histologic results were verified with a quantitative method for tissue triglyceride measurement; results appear in D. *p

Figure 5. Menopause decreases expression of genes…

Figure 5. Menopause decreases expression of genes associated with hepatic fatty acid oxidation and BB…

Figure 5. Menopause decreases expression of genes associated with hepatic fatty acid oxidation and BB supplementation prevents these changes
Relative expression levels of hepatic A) CD36, B) Cs, and C) Hadha in livers after 12 weeks of HFD or HFD supplemented with BB . **p<0.01, ****p<0.0001 vs. V group. C = cycling HFD control group, V = HFD+VCD, VB = HFD+BB+VCD, Cd36 = fatty acid translocase/CD36, Cs = citrate synthase, and Hadha = long-chain hydroxyacyl-CoA dehydrogenase.
Figure 5. Menopause decreases expression of genes…
Figure 5. Menopause decreases expression of genes associated with hepatic fatty acid oxidation and BB supplementation prevents these changes
Relative expression levels of hepatic A) CD36, B) Cs, and C) Hadha in livers after 12 weeks of HFD or HFD supplemented with BB . **p<0.01, ****p<0.0001 vs. V group. C = cycling HFD control group, V = HFD+VCD, VB = HFD+BB+VCD, Cd36 = fatty acid translocase/CD36, Cs = citrate synthase, and Hadha = long-chain hydroxyacyl-CoA dehydrogenase.

References

    1. CDC. Women's Reproductive Health: Menopause. U.S. Department of Health and Human Services; Jul 25, 2012. Available from: .
    1. Carr MC. The Emergence of the Metabolic Syndrome with Menopause. Journal of Clinical Endocrinology & Metabolism. 2003;88:2404–2411.
    1. Korytkowski MT, Krug EI, Daly MA, DeRiso L, Wilson JW, Winters SJ. Does androgen excess contribute to the cardiovascular risk profile in postmenopausal women with type 2 diabetes? Metabolism. 2005;54:1626–1631.
    1. Romero-Aleshire MJ, Diamond-Stanic MK, Hasty AH, Hoyer PB, Brooks HL. Loss of ovarian function in the VCD mouse-model of menopause leads to insulin resistance and a rapid progression into the metabolic syndrome. Am J Physiol Regul Integr Comp Physiol. 2009;297:R587–R592.
    1. Mayer LP, Devine PJ, Dyer CA, Hoyer PB. The Follicle-Deplete Mouse Ovary Produces Androgen. Biology of Reproduction. 2004;71:130–138.
    1. Lohff JC, Christian PJ, Marion SL, Arrandale A, Hoyer PB. Characterization of cyclicity and hormonal profile with impending ovarian failure in a novel chemical-induced mouse model of perimenopause. Comparative Medicine. 2005;55:523–527.
    1. Vuong T, Benhaddou-Andaloussi A, Brault A, Harbilas D, Martineau LC, Vallerand D, et al. Antiobesity and antidiabetic effects of biotransformed blueberry juice in KKAy mice. Int J Obes. 2009;33:1166–1173.
    1. Seymour EM, Tanone II, Urcuyo-Llanes DE, Lewis SK, Kirakosyan A, Kondoleon MG, et al. Blueberry Intake Alters Skeletal Muscle and Adipose Tissue Peroxisome Proliferator-Activated Receptor Activity and Reduces Insulin Resistance in Obese Rats. J Med Food. 2011;14:1511–1518.
    1. DeFuria J, Bennett G, Strissel KJ, Perfield JW, Milbury PE, Greenberg AS, et al. Dietary Blueberry Attenuates Whole-Body Insulin Resistance in High Fat-Fed Mice by Reducing Adipocyte Death and Its Inflammatory Sequelae. The Journal of Nutrition. 2009;139:1510–1516.
    1. Prior RL, Wu X, Gu L, Hager TJ, Hager A, Howard LR. Whole Berries versus Berry Anthocyanins: Interactions with Dietary Fat Levels in the C57BL/6J Mouse Model of Obesity. Journal of Agricultural and Food Chemistry. 2008;56:647–653.
    1. Mayer LP, Pearsall NA, Christian PJ, Devine PJ, Payne CM, McCuskey MK, et al. Long-term effects of ovarian follicular depletion in rats by 4-vinylcyclohexene diepoxide. Reproductive Toxicology. 2002;16:775–781.
    1. Nishikawa S, Yasoshima A, Doi K, Nakayama H, Uetsuka K. Involvement of Sex, Strain and Age Factors in High Fat Diet-Induced Obesity in C57BL/6J and BALB/cA Mice. Experimental Animals. 2007;56:263–272.
    1. Pettersson US, Waldén TB, Carlsson P-O, Jansson L, Phillipson M. Female Mice are Protected against High-Fat Diet Induced Metabolic Syndrome and Increase the Regulatory T Cell Population in Adipose Tissue. PLoS ONE. 2012;7:e46057.
    1. Beranger GE, Pisani DF, Castel J, Djedaini M, Battaglia S, Amiaud J, et al. Oxytocin Reverses Ovariectomy-Induced Osteopenia and Body Fat Gain. Endocrinology. 2014;155:1340–1352.
    1. Kanaya N, Vonderfecht S, Chen S. Androgen (dihydrotestosterone)–mediated regulation of food intake and obesity in female mice. The Journal of Steroid Biochemistry and Molecular Biology. 2013;138:100–106.
    1. Lovejoy JC, Champagne CM, de Jonge L, Xie H, Smith SR. Increased visceral fat and decreased energy expenditure during the menopausal transition. Int J Obes. 2008;32:949–958.
    1. Rogers NH, Perfield JW, II, Strissel KJ, Obin MS, Greenberg AS. Reduced Energy Expenditure and Increased Inflammation Are Early Events in the Development of Ovariectomy-Induced Obesity. Endocrinology. 2009;150:2161–2168.
    1. Yepuru M, Eswaraka J, Kearbey JD, Barrett CM, Raghow S, Veverka KA, et al. Estrogen Receptor-β-selective Ligands Alleviate High-fat Diet- and Ovariectomy-induced Obesity in Mice. Journal of Biological Chemistry. 2010;285:31292–31303.
    1. Kanaya N, Chen S. Conjugated linoleic acid reduces body weight gain in ovariectomized female C57BL/6J mice. Nutrition Research. 2010;30:714–721.
    1. Zhang J, Lazarenko OP, Blackburn ML, Shankar K, Badger TM, Ronis MJJ, et al. Feeding Blueberry Diets in Early Life Prevent Senescence of Osteoblasts and Bone Loss in Ovariectomized Adult Female Rats. PLoS ONE. 2011;6:e24486.
    1. Devareddy L, Hooshmand S, Collins JK, Lucas EA, Chai SC, Arjmandi BH. Blueberry prevents bone loss in ovariectomized rat model of postmenopausal osteoporosis. The Journal of Nutritional Biochemistry. 2008;19:694–699.
    1. Prior RLE, Wilkes SR, Rogers T, Khanal RC, Wu X, Howard LR. Purified Blueberry Anthocyanins and Blueberry Juice Alter Development of Obesity in Mice Fed an Obesogenic High-Fat Diet. Journal of Agricultural and Food Chemistry. 2010;58:3970–3976.
    1. D'Eon TM, Souza SC, Aronovitz M, Obin MS, Fried SK, Greenberg AS. Estrogen Regulation of Adiposity and Fuel Partitioning: EVIDENCE OF GENOMIC AND NON-GENOMIC REGULATION OF LIPOGENIC AND OXIDATIVE PATHWAYS. Journal of Biological Chemistry. 2005;280:35983–35991.
    1. Camporez JPG, Jornayvaz FR, Lee H-Y, Kanda S, Guigni BA, Kahn M, et al. Cellular Mechanism by Which Estradiol Protects Female Ovariectomized Mice From High-Fat Diet-Induced Hepatic and Muscle Insulin Resistance. Endocrinology. 2013;154:1021–1028.
    1. Szmuilowicz ED, Stuenkel CA, Seely EW. Influence of menopause on diabetes and diabetes risk. Nat Rev Endocrinol. 2009;5:553–558.
    1. Whitcroft S, Herriot A. Insulin resistance and management of the menopause: a clinical hypothesis in practice. Menopause International. 2011;17:24–28.
    1. Zhu L, Brown WC, Cai Q, Krust A, Chambon P, McGuinness OP, et al. Estrogen Treatment After Ovariectomy Protects Against Fatty Liver and May Improve Pathway-Selective Insulin Resistance. Diabetes. 2013;62:424–434.
    1. DeAngel RE, Berrigan D, Nunez NP, Hursting SD, Perkins SN. Dietary Calcium Source Influences Body Composition, Glucose Metabolism and Hormone Levels in a Mouse Model of Postmenopausal Obesity. In Vivo. 2009;23:527–535.
    1. Kim JH, Meyers MS, Khuder SS, Abdallah SL, Muturi HT, Russo L, et al. Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice. Molecular Metabolism. 2014;3:177–190.
    1. Stubbins R, Holcomb V, Hong J, Núñez N. Estrogen modulates abdominal adiposity and protects female mice from obesity and impaired glucose tolerance. Eur J Nutr. 2012;51:861–870.
    1. Kamada Y, Kiso S, Yoshida Y, Chatani N, Kizu T, Hamano M, et al. Estrogen deficiency worsens steatohepatitis in mice fed high-fat and high-cholesterol diet. Am J Physiol Gastrointest Liver Physiol. 2011;301:G1031–G1043.
    1. Jackson KC, Wohlers LM, Valencia AP, Cilenti M, Borengasser SJ, Thyfault JP, et al. Wheel running prevents the accumulation of monounsaturated fatty acids in the liver of ovariectomized mice by attenuating changes in SCD-1 content. Applied Physiology, Nutrition, and Metabolism. 2011;36:798–810.
    1. Elks CM, Francis J, Stull AJ, Cefalu WT, Shukitt-Hale B, Ingram DK. Bioactives in Fruit. John Wiley & Sons, Ltd; 2013. Overview of the Health Properties of Blueberries; pp. 251–271.
    1. Vendrame S, Daugherty A, Kristo AS, Klimis-Zacas D. Wild blueberry (Vaccinium angustifolium)-enriched diet improves dyslipidaemia and modulates the expression of genes related to lipid metabolism in obese Zucker rats. British Journal of Nutrition. 2014;111:194–200.
    1. Roopchand DE, Kuhn P, Rojo LE, Lila MA, Raskin I. Blueberry polyphenol-enriched soybean flour reduces hyperglycemia, body weight gain and serum cholesterol in mice. Pharmacological Research. 2013;68:59–67.
    1. Paquette A, Chapados NA, Bergeron R, Lavoie JM. Fatty Acid Oxidation is Decreased in the Liver of Ovariectomized Rats. Horm Metab Res. 2009;41:511–515.
    1. Enos RT, Velázquez KT, Murphy EA. Insight into the impact of dietary saturated fat on tissue-specific cellular processes underlying obesity-related diseases. The Journal of Nutritional Biochemistry. 2014;25:600–612.
    1. Perry RJ, Samuel VT, Petersen KF, Shulman GI. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature. 2014;510:84–91.

Source: PubMed

3
Subscribe