Insulin and adipokine signaling and their cross-regulation in postmortem human brain

Hoau Yan Wang, Ana W. Capuano, Amber Khan, Zhe Pei, Kuo Chieh Lee, David A. Bennett, Rexford S. Ahima, Steven E. Arnold, Zoe Arvanitakis

Research output: Contribution to journalArticlepeer-review

Abstract

Aberrant insulin and adipokine signaling has been implicated in cognitive decline associated with both type 2 diabetes mellitus and neurodegenerative diseases. We established methods that reliably measure insulin, adiponectin and leptin signaling, and their crosstalk, in thawed postmortem mid-frontal cortical tissue from cognitively normal older subjects with a short postmortem interval. Insulin-evoked insulin receptor (IR) activation increases activated, tyrosine-phosphorylated IRβ on tyrosine residues 960, 1150, and 1151, insulin receptor substrate-1 recruitment to IRβ and phosphorylated RAC-α-serine/threonine-protein kinase. Adiponectin augments, but leptin inhibits, insulin signaling. Adiponectin activates adiponectin receptors to induce APPL1 binding to adiponectin receptor 1 and 2 and T-cadherin and downstream adenosine monophosphate–dependent protein kinase phosphorylation. Insulin inhibited adiponectin-induced signaling. In addition, leptin-induced leptin receptor (OB-R) signaling promotes Janus kinase 2 recruitment to OB-R and Janus kinase 2 and downstream signal transducer and activator of transcription 3 phosphorylation. Insulin enhanced leptin signaling. These data demonstrate insulin and adipokine signaling interactions in human brain. Future studies can use these methods to examine insulin, adiponectin, and leptin metabolic dysregulation in aging and disease states, such as type 2 diabetes and Alzheimer's disease–related dementias.

Original languageEnglish (US)
Pages (from-to)119-130
Number of pages12
JournalNeurobiology of aging
Volume84
DOIs
StatePublished - Dec 2019

Keywords

  • Adipokine
  • Adiponectin receptors
  • Alzheimer's disease–related dementias
  • Leptin receptors
  • Postmortem brain
  • Type 2 diabetes
  • insulin signaling

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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