Adipocyte-specific deletion of Ip6k1 reduces diet-induced obesity by enhancing AMPK-mediated thermogenesis
Qingzhang Zhu, … , James C. Barrow, Anutosh Chakraborty
Qingzhang Zhu, … , James C. Barrow, Anutosh Chakraborty
Published October 4, 2016
Citation Information: J Clin Invest. 2016;126(11):4273-4288. https://doi.org/10.1172/JCI85510.
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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

Qingzhang Zhu, Sarbani Ghoshal, Ana Rodrigues, Su Gao, Alice Asterian, Theodore M. Kamenecka, James C. Barrow, Anutosh Chakraborty

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Figure 8

Thermoneutrally placed HFD-AdKO mice do not display leanness but exhibit insulin sensitivity.

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Thermoneutrally placed HFD-AdKO mice do not display leanness but exhibit...
(A) AdKOs, when fed a HFD at thermoneutral (30°C) temperature, gain body weight at a similar rate compared with LoxPs (n = 6 mice per group; 2-way ANOVA). (B) AdKOs at 23°C (8 weeks of HFD) display a reduced weight gain compared with LoxPs, whereas AdKOs at 30°C gain similar body weight compared with LoxPs (n = 6 mice per group; t test). (C) Total fat, lean, and fluid masses are similar in LoxPs and AdKOs after 8 weeks of HFD feeding at 30°C (n = 6 mice per group; t test). (D) EE is similar in AdKOs and LoxPs at 30°C (8 weeks of HFD) (n = 6 mice per group; t test). (E) Adipose tissue browning and mitochondrial markers are similar in HFD-fed LoxPs and AdKOs, after 14 weeks of HFD at thermoneutrality (n = 6 mice per group; t test). (F) After 14 weeks of HFD at 30°C, AdKOs display improved GTT compared with LoxPs (n = 6 per group; 2-way ANOVA). (G) AUC analyses reveal that AdKOs, after 14 weeks of HFD at 30°C, efficiently dispose glucose compared with LoxPs (n = 6 mice per group; t test). (H) Akt stimulatory (S473) phosphorylation is 4- to 5-fold higher in AdKO liver and EWAT after 14 weeks of HFD feeding at 30°C (n = 4 mice per group). Data in all panels are expressed as mean ± SEM. *P < 0.05, **P < 0.01, #P < 0.001.