APPL1
DCC-interacting protein 13-alpha (Dip13-alpha) (Adapter protein containing PH domain, PTB domain and leucine zipper motif 1) [APPL] [DIP13A] [KIAA1428]
Publications[править]
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.
MeSH Terms
- Adipokines
- Aging
- Brain
- Humans
- Insulin
- Leptin
- Postmortem Changes
- Signal Transduction
Keywords
- Adipokine
- Adiponectin receptors
- Alzheimer's disease–related dementias
- Leptin receptors
- Postmortem brain
- Type 2 diabetes
- insulin signaling
The primary purpose of this study was to assess the feasibility of applying a novel approach to measure myosin heavy chain (MHC) isoform expression, glucose uptake, fiber volume, and protein abundance in single muscle fibers of adult (9 months) and old (25 months) rats. Epitrochlearis muscle fibers were successfully isolated and analyzed for MHC isoform expression, glucose uptake, fiber volume, and protein (COXIV, APPL1, IκB-β) abundance. Insulin-stimulated glucose uptake by single fibers did not differ between age groups, but there was a significant difference between fiber types (IIA > IIX > IIB/X ≈ IIB). There were also significant main effects of fiber type on APPL1 (IIX > IIB) and COXIV (IIA > IIX > IIB/X ≈ IIB) abundance, and IIB fibers were significantly larger than IIA fibers. This study established the feasibility of a new approach for assessing age-related differences in muscle at the single-fiber level and demonstrated the magnitude and rank order for fiber-type differences in insulin-stimulated glucose uptake of 9-month-old and 25-month-old rats.
MeSH Terms
- Aging
- Animals
- Feasibility Studies
- Glucose
- Immunoblotting
- In Vitro Techniques
- Insulin Resistance
- Male
- Muscle Fibers, Fast-Twitch
- Muscle Fibers, Slow-Twitch
- Myosin Heavy Chains
- Protein Isoforms
- Rats
- Rats, Inbred Strains
- Sarcopenia