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 3

Adipocyte-specific Ip6k1 deletion protects mice from HFD-induced insulin resistance.

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Adipocyte-specific Ip6k1 deletion protects mice from HFD-induced insulin...
(A) Blood glucose level is lower in ad libitum HFD-AdKOs. Overnight fasting decreases blood glucose level in HFD-AdKOs but not in corresponding HFD-LoxPs (n = 8 mice per group; t test). (B) Improved glucose disposal (GTT) in HFD-AdKOs (n = 8–10 mice per group; 2-way ANOVA). (C) Improved glucose disposal in HFD-AdKOs following insulin injection (ITT) (n = 8–10 mice per group; 2-way ANOVA). (D) AUC analyses of B and C confirm enhanced glucose and insulin tolerances in HFD-AdKOs (n = 8–10 mice per group; t test). (E) HFD-AdKOs exhibit reduced plasma insulin level (n = 8 mice per group; t test). (F) Akt (S473) stimulatory phosphorylation is substantially higher in the EWAT, liver, and gastrocnemius muscle of HFD-AdKOs (n = 4 mice per group). (G) ImageJ quantification of F reveals that Akt stimulatory phosphorylation (S473) is 4- to 6-fold higher in EWAT, gastrocnemius muscle, and liver of HFD-AdKOs (t test). p/T, phosphorylated Akt/total Akt. (H) Plasma levels of HMW and total but not LMW ADIPOQ are higher in HFD-AdKOs (n = 7 mice per group). (I) ImageJ quantification of H reveals that the plasma level of HMW-ADIPOQ is 2.5-fold higher in HFD-AdKOs (t test). (J) ImageJ quantification of H demonstrates a 2-fold increase in the plasma level of total ADIPOQ in HFD-AdKOs (t test). Data in all panels are expressed as mean ± SEM. *P < 0.05, **P < 0.01, §P < 0.0001.