title: Adipocyte-specific deletion of Ip6k1 reduces diet-induced obesity by enhancing AMPK-mediated thermogenesis.
abstract: Enhancing energy expenditure (EE) is an attractive strategy to combat obesity and diabetes. Global deletion of Ip6k1 protects mice from diet-induced obesity (DIO) and insulin resistance, but the tissue-specific mechanism by which IP6K1 regulates body weight is unknown. Here, we have demonstrated that IP6K1 regulates fat accumulation by modulating AMPK-mediated adipocyte energy metabolism. Cold exposure led to downregulation of Ip6k1 in murine inguinal and retroperitoneal white adipose tissue (IWAT and RWAT) depots. Adipocyte-specific deletion of Ip6k1 (AdKO) enhanced thermogenic EE, which protected mice from high-fat diet-induced weight gain at ambient temperature (23°C), but not at thermoneutral temperature (30°C). AdKO-induced increases in thermogenesis also protected mice from cold-induced decreases in body temperature. UCP1, PGC1α, and other markers of browning and thermogenesis were elevated in IWAT and RWAT of AdKO mice. Cold-induced activation of sympathetic signaling was unaltered, whereas AMPK was enhanced, in AdKO IWAT. Moreover, beige adipocytes from AdKO IWAT displayed enhanced browning, which was diminished by AMPK depletion. Furthermore, we determined that IP6 and IP6K1 differentially regulate upstream kinase-mediated AMPK stimulatory phosphorylation in vitro. Finally, treating mildly obese mice with the IP6K inhibitor TNP enhanced thermogenesis and inhibited progression of DIO. Thus, IP6K1 regulates energy metabolism via a mechanism that could potentially be targeted in obesity.
authors.forename: Qingzhang
authors.initials: Q
authors.lastname: Zhu
authors.forename: Sarbani
authors.initials: S
authors.lastname: Ghoshal
authors.forename: Ana
authors.initials: A
authors.lastname: Rodrigues
authors.forename: Su
authors.initials: S
authors.lastname: Gao
authors.forename: Alice
authors.initials: A
authors.lastname: Asterian
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.forename: James C
authors.initials: JC
authors.lastname: Barrow
authors.forename: Anutosh
authors.initials: A
authors.lastname: Chakraborty
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D052438:Adipocytes, White / Q000378:metabolism* / Q000473:pathology; D052436:Adipose Tissue, White / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004734:Energy Metabolism / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D022722:Thermogenesis; D000071256:Uncoupling Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: C485444:Ihpk1 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D055372:AMP-Activated Protein Kinases; D017856:Phosphotransferases (Phosphate Group Acceptor)