Pid1 induces insulin resistance in both human and mouse skeletal muscle during obesity.
Obesity is associated with insulin resistance and abnormal peripheral tissue glucose uptake. However, the mechanisms that interfere with insulin signaling and glucose uptake in human skeletal muscle during obesity are not fully characterized. Using microarray, we have identified that the expression of Pid1 gene, which encodes for a protein that contains a phosphotyrosine-interacting domain, is increased in myoblasts established from overweight insulin-resistant individuals. Molecular analysis further validated that both Pid1 mRNA and protein levels are increased in cell culture models of insulin resistance. Consistent with these results, overexpression of phosphotyrosine interaction domain-containing protein 1 (PID1) in human myoblasts resulted in reduced insulin signaling and glucose uptake, whereas knockdown of PID1 enhanced glucose uptake and insulin signaling in human myoblasts and improved the insulin sensitivity following palmitate-, TNF-α-, or myostatin-induced insulin resistance in human myoblasts. Furthermore, the number of mitochondria in myoblasts that ectopically express PID1 was significantly reduced. In addition to overweight humans, we find that Pid1 levels are also increased in all 3 peripheral tissues (liver, skeletal muscle, and adipose tissue) in mouse models of diet-induced obesity and insulin resistance. An in silico search for regulators of Pid1 expression revealed the presence of nuclear factor-κB (NF-κB) binding sites in the Pid1 promoter. Luciferase reporter assays and chromatin immunoprecipitation studies confirmed that NF-κB is sufficient to transcriptionally up-regulate the Pid1 promoter. Furthermore, we find that myostatin up-regulates Pid1 expression via an NF-κB signaling mechanism. Collectively these results indicate that Pid1 is a potent intracellular inhibitor of insulin signaling pathway during obesity in humans and mice.
School of Biological Sciences, Nanyang Technological University, Singapore 637551.
Sabeera
S
Bonala
Craig
C
McFarlane
Jackie
J
Ang
Radiance
R
Lim
Marcus
M
Lee
Hillary
H
Chua
Sudarsanareddy
S
Lokireddy
Patnam
P
Sreekanth
Melvin Khee Shing
MK
Leow
Khoo Chin
KC
Meng
Tai E
TE
Shyong
Yung Seng
YS
Lee
Peter D
PD
Gluckman
Mridula
M
Sharma
Ravi
R
Kambadur
D000328:Adult; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055435:Myostatin / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000473:pathology*; D019308:Palmitic Acid / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D055815:Young Adult
D002352:Carrier Proteins; D007328:Insulin; D055435:Myostatin; D016328:NF-kappa B; C556403:NYGGF4 protein, mouse; C514653:PID1 protein, human; D020033:Protein Isoforms; D014409:Tumor Necrosis Factor-alpha; D019308:Palmitic Acid