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Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1

Masato Iwabu1, Toshimasa Yamauchi, Miki Okada-Iwabu

  • 1Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.

Nature
|April 2, 2010
PubMed

Insights

Adiponectin, via its receptor AdipoR1, triggers calcium influx, activating key metabolic pathways. This process is crucial for mitochondrial health, exercise endurance, and combating insulin resistance in skeletal muscle.

Area of Science:

  • Metabolic signaling
  • Mitochondrial biogenesis
  • Adipokine research

Background:

  • Adiponectin is an anti-diabetic adipokine.
  • Adiponectin receptors (AdipoRs) differ from typical G-protein-coupled receptors.
  • Understanding AdipoR1's signaling is key to metabolic disease research.

Purpose of the Study:

  • To investigate the role of adiponectin receptor 1 (AdipoR1) in mediating adiponectin's effects on cellular metabolism.
  • To elucidate the signaling cascade initiated by AdipoR1 activation.
  • To determine the impact of AdipoR1 function on skeletal muscle mitochondria, insulin sensitivity, and exercise performance.

Main Methods:

  • Investigated adiponectin-induced extracellular Ca(2+) influx via AdipoR1.
  • Assessed the activation of Ca(2+)/calmodulin-dependent protein kinase kinase beta (CaMKKbeta), AMPK, and SIRT1.
  • Examined changes in peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) expression and acetylation.
  • Utilized muscle-specific AdipoR1 disruption models in mice.
  • Measured mitochondrial content, enzyme activity, myofiber type distribution, and oxidative stress markers.

Main Results:

  • Adiponectin binding to AdipoR1 induced extracellular Ca(2+) influx, essential for activating CaMKKbeta, AMPK, and SIRT1.
  • This signaling cascade led to increased PGC-1alpha expression, decreased acetylation, and enhanced mitochondrial biogenesis in myocytes.
  • Muscle-specific AdipoR1 disruption abolished adiponectin's effects on intracellular Ca(2+) and downstream signaling pathways (CaMKK, AMPK, SIRT1).
  • AdipoR1 suppression resulted in reduced PGC-1alpha activity, decreased mitochondrial function, altered myofiber type, and diminished oxidative stress defenses.
  • These molecular changes correlated with insulin resistance and impaired exercise endurance.

Conclusions:

  • AdipoR1 is critical for adiponectin's beneficial effects on skeletal muscle metabolism and function.
  • The adiponectin-AdipoR1 axis regulates intracellular calcium, mitochondrial biogenesis, and insulin sensitivity.
  • Dysfunctional adiponectin and AdipoR1 signaling in obesity may contribute to mitochondrial dysfunction and insulin resistance in type 2 diabetes.

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