Stöhr, Oliver (2012) Role of insulin receptor substrate 1 in energy homeostasis in vivo. PhD thesis, Universität zu Köln.
Insulin and insulin-like growth factor-1 receptor signaling plays a crucial role in regulation of growth, lifespan and energy homeostasis. Insulin receptor substrates (IRS) mediate intracellular effects of the insulin and insulin-like growth factor-1 receptor. IRS-1 deficient mice (IRS-1-/-) display dwarfism, increased food intake, elevated energy expenditure and reduced accumulation of epigonadal fat compared to wild-type littermates. To investigate the molecular basis of increased energy expenditure activity of respiratory chain complexes were determined. Mitochondrial performance was analyzed in liver, musculus soleus, musculus gastrocnemius, embryonic fibroblast (MEF) of wild-type and IRS-1 knockout mice as well as mitochondria isolated from MEFs using different techniques. The molecular mechanism of elevated food intake of IRS-1 deficient mice was addressed by Real-time PCR analysis of hypothalamic neuropeptides. Determination of mitochondrial respiratory chain complex activities revealed no significant and consistent alteration in mitochondrial performance in muscle and liver of IRS-1 knockout mice compared to wild-type controls. Additionally no mitochondrial dysfunction was detected on the cellular level analyzing MEFs and isolated mitochondria. However, complex V activities in liver and musculus soleus IRS-1-/- males were significantly decreased. Additionally female knockout mice showed decreased performance of complex V in musculus soleus. Determination of mitochondrial respiratory chain coupling using proton motive force measurements revealed enhanced uncoupling in the IRS-1-/- mice. This was supported by Real-time PCR analysis of uncoupling protein expression in different tissues. Furthermore elevated food intake in the IRS-1 deficient mice was linked to enhanced expression of orectic neuropeptides in hypothalamus in these mice. Taken together the results of present study indicate enhanced uncoupling in IRS-1 deficient mice as underlying mechanism for increased energy expenditure. Elevated food intake of IRS-1 knockout mice might be a consequence of increased energy expenditure leading to enhanced expression of orectic neuropetides NPY/AgRP providing adequate supply of metabolic fuel (e.g. glucose) in knockout mice in response to higher energy demand.
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