The prevalence of obesity-related comorbidities such as type-2 diabetes and heart diseases in the US emphasizes the need for concerted efforts to prevent and treat obesity1-3. A decrease in 5% of body weight significantly reduces cardiovascular risk in humans4 which proves the urgency of weight management. A combination of drug and lifestyle intervention is ideal for obesity management5-8. Unfortunately, the current anti-obesity medications that inhibit food intake or absorption are partly effective9,10. Thus, an alternate approach is to target energy metabolism11-19 due to the fact that obesity results when energy storage in the adipose tissue exceeds its expenditure20. However, due to the complexity of adipose tissue21, the fundamental…show more content… Accordingly, AMPK, PGC1and their thermogenic target, the uncoupling protein 1 (UCP1) are dramatically upregulated in K1-KO adipose tissues. Moreover, IP6K1 generated IP7 inhibits AMPK activity in vitro. Based on these preliminary results, our working hypothesis is that IP6K1 regulates energy metabolism by inhibiting the AMPK-PGC1 pathway. To test this, we will measure core body temperature; -oxidation and browning in adipose depots of K1-KO mice fed a high fat diet or exposed to cold stress. We will measure -oxidation and mitochondrial respiration in K1-KO adipocytes and in inducible IP6K1 knock-down adipocyte cell lines. Utilizing enzyme assays and hydrogen deuterium exchange (HDX) studies, we will determine the molecular mechanism by which IP6K1/IP7 inhibits AMPK. Furthermore, we will monitor the AMPK stimulator; 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) mediated -oxidation and insulin sensitivity in K1-KO mice. Successful completion of this aim will establish IP6K1 as a novel regulator of energy expenditure.
Aim 2: Identify functions of IP6K1 in lipolysis. K1-KO mice exhibit enhanced fasting induced weight loss. They also display enhanced basal lipolysis and downregulation of the lipolytic modulator perilipin1 (PLIN1) in the adipose tissues. IP6K1 possesses a lipase motif by which it binds and stabilizes PLIN1. PKA (Protein kinase A) phosphorylates IP6K1 especially during -adrenergic receptor (-AR)