Resistin has been suggested to be involved in the development of diabetes and
insulin resistance. We recently reported that
resistin is expressed in diabetic hearts and promotes
cardiac hypertrophy; however, the mechanisms underlying this process are currently unknown. Therefore, we wanted to elucidate the mechanisms associated with
resistin-induced
cardiac hypertrophy and myocardial
insulin resistance. Overexpression of
resistin using adenoviral vector in neonatal rat ventricular myocytes was associated with inhibition of
AMP-activated protein kinase (AMPK) activity, activation of
tuberous sclerosis complex 2/
mammalian target of rapamycin (mTOR) pathway, and increased cell size, [(3)H]
leucine incorporation (i.e.
protein synthesis) and
mRNA expression of the hypertrophic marker genes,
atrial natriuretic factor,
brain natriuretic peptide, and β-
myosin heavy chain. Activation of AMPK with 5-aminoimidazole-4-carbozamide-1-β-D-ribifuranoside or inhibition of mTOR with
rapamycin or mTOR
siRNA attenuated these
resistin-induced changes. Furthermore,
resistin increased
serine phosphorylation of
insulin receptor substrate (IRS1) through the activation of the
apoptosis signal-regulating kinase 1/
c-Jun N-terminal Kinase (JNK) pathway, a module known to stimulate
insulin resistance. Inhibition of JNK (with JNK inhibitor
SP600125 or using dominant-negative JNK) reduced
serine 307 phosphorylation of IRS1.
Resistin also stimulated the activation of p70(S6K), a downstream
kinase target of mTOR, and increased phosphorylation of the IRS1
serine 636/639 residues, whereas treatment with
rapamycin reduced the phosphorylation of these residues. Interestingly, these in vitro signaling pathways were also operative in vivo in ventricular tissues from adult rat hearts overexpressing
resistin. These data demonstrate that
resistin induces
cardiac hypertrophy and myocardial
insulin resistance, possibly via the AMPK/mTOR/p70(S6K) and
apoptosis signal-regulating kinase 1/JNK/IRS1 pathways.