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High dietary fat and sucrose results in an extensive and time-dependent deterioration in health of multiple physiological systems in mice

Abstract

Obesity is associated with metabolic dysfunction, including insulin resistance and hyperinsulinemia, and with disorders such as cardiovascular disease, osteoporosis, and neurodegeneration. Typically, these pathologies are examined in discrete model systems and with limited temporal resolution, and whether these disorders co-occur is therefore unclear. To address this question, we examined multiple physiological systems in male C57BL/6J mice following prolonged exposure to a high-fat/high-sucrose diet (HFHSD). HFHSD-fed mice rapidly exhibited metabolic alterations, including obesity, hyperleptinemia, physical inactivity, glucose intolerance, peripheral insulin resistance, fasting hyperglycemia, ectopic lipid deposition, and bone deterioration. Prolonged exposure to HFHSD resulted in morbid obesity, ectopic triglyceride deposition in liver and muscle, extensive bone loss, sarcopenia, hyperinsulinemia, and impaired short-term memory. Although many of these defects are typically associated with aging, HFHSD did not alter telomere length in white blood cells, indicating that this diet did not generally promote all aspects of aging. Strikingly, glucose homeostasis was highly dynamic. Glucose intolerance was evident in HFHSD-fed mice after 1 week and was maintained for 24 weeks. Beyond 24 weeks, however, glucose tolerance improved in HFHSD-fed mice, and by 60 weeks, it was indistinguishable from that of chow-fed mice. This improvement coincided with adaptive beta-cell hyperplasia and hyperinsulinemia, without changes in insulin sensitivity in muscle or adipose tissue. Assessment of insulin secretion in isolated islets revealed that leptin, which inhibited insulin secretion in the chow-fed mice, potentiated glucose-stimulated insulin secretion in the HFHSD-fed mice after 60 weeks. Overall, the excessive calorie intake was accompanied by deteriorating function of numerous physiological systems.

Type Journal
ISBN 1083-351X (Electronic) 0021-9258 (Linking)
Authors Burchfield, J. G.; Kebede, M. A.; Meoli, C. C.; Stockli, J.; Whitworth, P. T.; Wright, A. L.; Hoffman, N. J.; Minard, A. Y.; Ma, X.; Krycer, J. R.; Nelson, M. E.; Tan, S. X.; Yau, B.; Thomas, K. C.; Wee, N. K. Y.; Khor, E. C.; Enriquez, R. F.; Vissel, B.; Biden, T. J.; Baldock, P. A.; Hoehn, K. L.; Cantley, J.; Cooney, G. J.; James, D. E.; Fazakerley, D. J.
Responsible Garvan Author Prof Trevor Biden
Publisher Name JOURNAL OF BIOLOGICAL CHEMISTRY
Published Date 2018-02-15
Status Published in-print
DOI 10.1074/jbc.RA117.000808
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/29440390