Maternal high-fat diet induces long-term obesity with sex-dependent metabolic programming of adipocyte differentiation, hypertrophy and dysfunction in the offspring

Maternal obesity determines obesity and metabolic diseases in the offspring. The white adipose tissue (WAT) orchestrates metabolic pathways, and its dysfunction contributes to metabolic disorders in a sex-dependent manner. Here, we tested if sex differences influence the molecular mechanisms of metabolic programming of WAT in offspring of obese dams. To this end, maternal obesity was induced with high-fat diet (HFD) and the offspring were studied at an early phase [postnatal day 21 (P21)], a late phase (P70) and finally P120. In the early phase we found a sex-independent increase in WAT in offspring of obese dams using magnetic resonance imaging (MRI), which was more pronounced in females than males. While the adipocyte size increased in both sexes, the distribution of WAT differed in males and females. As mechanistic hints, we identified an inflammatory response in females and a senescence-associated reduction in the preadipocyte factor DLK in males. In the late phase, the obese body composition persisted in both sexes, with a partial reversal in females. Moreover, female offspring recovered completely from both the adipocyte hypertrophy and the inflammatory response. These findings were linked to a dysregulation of lipolytic, adipogenic and stemness-related markers as well as AMPKalpha and Akt signaling. Finally, the sex-dependent metabolic programming persisted with sex-specific differences in adipocyte size until P120. In conclusion, we do not only provide new insights into the molecular mechanisms of sex-dependent metabolic programming of WAT dysfunction, but also highlight the sex-dependent development of low- and high-grade pathogenic obesity.

  • Litzenburger, T.
  • Huber, E. K.
  • Dinger, K.
  • Wilke, R.
  • Vohlen, C.
  • Selle, J.
  • Kadah, M.
  • Persigehl, T.
  • Heneweer, C.
  • Dotsch, J.
  • Alejandre Alcazar, M. A.

Keywords

  • Adipocytes, White/*metabolism/pathology
  • *Adipogenesis/genetics
  • Adipose Tissue, White/*metabolism/pathology/physiopathology
  • *Adiposity/genetics
  • Animal Nutritional Physiological Phenomena
  • Animals
  • Cell Size
  • *Diet, High-Fat
  • Disease Models, Animal
  • *Energy Metabolism/genetics
  • Female
  • Gene Expression Regulation
  • Hypertrophy
  • Male
  • Maternal Nutritional Physiological Phenomena
  • Mice, Inbred C57BL
  • Nutritional Status
  • Obesity, Maternal/genetics/*metabolism/pathology/physiopathology
  • Pregnancy
  • *Prenatal Exposure Delayed Effects
  • Sex Characteristics
  • Sex Factors
  • Signal Transduction
  • Time Factors
  • *adipose tissue dysfunction
  • *maternal obesity
  • *metabolic programming
  • *sex-dependent differences
  • *white adipose tissue
Publication details
DOI: 10.1042/CS20191229
Journal: Clin Sci (Lond)
Pages: 921-939
Number: 7
Work Type: Original
Access number: 32239178
See publication on PubMed
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