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PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

David Garcia-Galiano1, Beatriz C Borges1,2, Jose Donato3

  • 1Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.

JCI Insight
|December 8, 2017
PubMed

Insights

Disrupting PI3K in leptin receptor cells boosts energy expenditure but impairs growth and reproduction. These effects are independent of insulin signaling, clarifying PI3K

Area of Science:

  • Metabolic Regulation
  • Endocrinology
  • Molecular Biology

Background:

  • The precise role of phosphatidylinositol 3-kinase (PI3K) in leptin physiology is complex, partly due to its downstream signaling from multiple metabolic cues like insulin.
  • Investigating PI3K's function in leptin receptor (LR) cells requires dissecting the contributions of specific PI3K catalytic subunits and the insulin receptor (InsR).

Discussion:

  • Disruption of p110α and p110β PI3K subunits in LR cells (LRΔα+β) led to a lean phenotype characterized by increased energy expenditure, locomotor activity, and thermogenesis.
  • While LRΔα+β mice exhibited deficient growth and delayed puberty, single subunit deletions (e.g., p110α in LRΔα) showed similar metabolic effects but differential impacts on activity and thermogenesis.
  • Reduced PI3K signaling in LR cells enhanced leptin sensitivity for metabolic control, evidenced by increased hypothalamic pAKT, leptin-induced pSTAT3, and decreased PTEN, yet growth and puberty remained unresponsive.

Key Insights:

  • PI3K signaling within leptin receptor cells is crucial for regulating energy expenditure, growth, and reproductive functions.
  • The metabolic and growth/reproductive roles of PI3K in LR cells are distinct and operate independently of insulin receptor signaling.
  • Specific PI3K subunits (p110α, p110β) differentially contribute to leptin's physiological effects.

Outlook:

  • Further research can elucidate the specific downstream pathways mediating PI3K's distinct roles in energy balance versus growth and reproduction.
  • Understanding these PI3K-dependent pathways could reveal novel therapeutic targets for metabolic disorders and reproductive health issues.
Keywords:
Bone developmentFertilityLeptinReproductive Biology

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