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 1

Adipocyte-specific Ip6k1-deleted mice accumulate less fat because of enhanced thermogenic EE under chow-fed conditions.

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Adipocyte-specific Ip6k1-deleted mice accumulate less fat because of enh...
(A) Generation of AdKOs. Details of the knockout generation strategy are described in Methods. (B) Immunoblot analyses confirm deletion of IP6K1 protein from various adipose tissue depots. Detection of residual IP6K1 is due to the presence of macrophages and other immune cells in the adipose tissue. Liver samples from AdKO mice were run as a control. BAT and liver samples were run on a separate gel. Blot represents data from 3 independent experiments. (C) CD-AdKOs (8 weeks old) display significantly reduced percentage fat mass (n = 10 mice per group; t test). (D) Weights of diverse adipose tissue depots are marginally less in CD-AdKOs (n = 4 mice per group; t test). (E) VO2 is higher in CD-AdKOs at 23°C and following cold and cold + fasting exposures (n = 8 mice per group). (F and G) EE is higher in CD-AdKOs under the above-mentioned conditions (n = 8 mice per group; t test). (H) CD-AdKOs consume more oxygen to oxidize carbohydrate at 23°C and 5°C (n = 8 mice per group; t test). (I) Following acute fasting at 5°C, CD-AdKOs consume more oxygen for fat oxidation (n = 8 mice per group; t test). (J) CD-AdKOs maintain body temperature more efficiently than LoxPs following acute cold + fasting exposure (n = 8 mice per group; 2-way ANOVA). (K) CD-AdKOs are also partly protected against drop in body temperature induced by chronic cold (3 days) and acute cold + fasting (n = 8 mice per group; 2-way ANOVA). (L) Ip6k1 is the major Ip6k isoform in the adipose tissue, which is downregulated by acute cold exposure in IWAT and RWAT. Ip6k1 expression is lower in the BAT and is not further reduced by cold (n = 5 mice per group; 2-way ANOVA). (M) Chronic cold also specifically reduces Ip6k1 expression in IWAT (n = 6 mice per group; t test). Data in all panels are expressed as mean ± SEM. *P < 0.05, **P < 0.01, #P < 0.001, §P < 0.0001.