Ablation of AMPK-Related Kinase MPK38/MELK Leads to Male-Specific Obesity in Aged Mature Adult Mice

Diabetes. 2021 Feb;70(2):386-399. doi: 10.2337/db20-0436. Epub 2020 Dec 2.

Abstract

Murine protein serine-threonine kinase 38 (MPK38)/maternal embryonic leucine zipper kinase (MELK) is implicated in diverse biological processes, including the cell cycle, apoptosis, and tumorigenesis; however, its physiological role is unknown. Using mice lacking MPK38 (MPK38-/-), we found that MPK38-/- male, but not female, mice (7 months of age) became obese while consuming a standard diet, displayed impairments in metabolism and inflammation, became more obese than wild-type mice while consuming a high-fat diet, and exhibited no castration/testosterone replacement-induced metabolic changes. The adenoviral restoration of MPK38 ameliorated the obesity-induced adverse metabolic profile of the obese male, but not female, mice. Seven-month-old MPK38-/- males displayed typical postcastration concentrations of serum testosterone with an accompanying decrease in serum luteinizing hormone (LH) levels, suggesting a role for MPK38 in the age-related changes in serum testosterone in aged mature adult male mice. The stability and activity of MPK38 were increased by dihydrotestosterone but reduced by estradiol (E2). These findings suggest MPK38 as a therapeutic target for obesity-related metabolic disorders in males.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Diet, High-Fat
  • Estradiol / blood
  • Fatty Acids, Nonesterified / blood
  • Female
  • Glucose Tolerance Test
  • Insulin / blood
  • Lipogenesis / physiology
  • Luteinizing Hormone / blood
  • Male
  • Mice
  • Mice, Knockout
  • Obesity / genetics*
  • Obesity / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Sex Factors
  • Testosterone / blood

Substances

  • Blood Glucose
  • Fatty Acids, Nonesterified
  • Insulin
  • Testosterone
  • Estradiol
  • Luteinizing Hormone
  • Melk protein, mouse
  • Protein Serine-Threonine Kinases

Associated data

  • figshare/10.2337/figshare.13259669