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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Concise Communication Metabolism

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 2

Increased thermogenic EE decelerates HFD-induced weight gain in AdKO mice.

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Increased thermogenic EE decelerates HFD-induced weight gain in AdKO mic...
(A) Average weekly weight gain is less in HFD-AdKOs (n = 15 mice per group; 2-way ANOVA). (B) Representative photographs of mice (from A) demonstrate that after 14 weeks of HFD feeding, AdKOs appear smaller and accumulate less fat. (C) After 8 weeks of HFD feeding, AdKOs display less fat mass. Lean/fluid masses are less altered (n = 10 mice per group; t test). (D) Representative photographs (from mice used in A) reveal that EWAT, RWAT, and IWAT appear smaller in HFD-AdKOs. (E) AdKOs are protected against HFD-induced adipocyte hypertrophy. AdKO BAT accumulates less fat (image represents data from n = 3 mice per group). (F) AdKOs are protected against HFD-induced fatty liver (image represents data from n = 3 mice per group). (G) AdKOs (8 weeks of HFD at 23°C) display higher VO2 consumption at 23°C, which is further enhanced following cold exposure (n = 8 mice per group). (H) Average cold-induced EE is higher in HFD-AdKOs (n = 8 mice per group; t test). (I) HFD-AdKOs consume more oxygen to oxidize carbohydrate at 23°C. However, at 5°C, they oxidize carbohydrate to a similar extent (n = 8 mice per group; t test). (J) HFD-AdKOs consume similar oxygen for fat oxidation at 23°C. However, AdKOs oxidize more fat at 5°C and following acute fasting at 5°C (n = 8 mice per group; t test). Data in all panels are expressed as mean ± SEM. *P < 0.05, **P < 0.01, §P < 0.0001.