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 7

IP6 and IP6K1 differentially regulate AMPK stimulatory phosphorylation.

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IP6 and IP6K1 differentially regulate AMPK stimulatory phosphorylation. ...
(A) Immunoblot demonstrates that overexpression of GST-IP6K1 diminishes AMPK and ACC phosphorylation levels in HEK293 cells under basal (+), glucose-deprived (–), and glucose-reintroduced (–/+) conditions. Data represent results from at least 3 independent experiments. (B) IP6, at increasing concentrations, stimulates AMPKα2/β1/γ1 (AMPKα T172) phosphorylation mediated by LKB1-only (120 ng/reaction). Data represent results from at least 3 independent experiments. (C) Quantification of B reveals that IP6 leads to 6- to 7-fold enhancements in LKB1-mediated AMPK phosphorylation in vitro. Data represent results from at least 3 independent experiments (1-way ANOVA). (D) Among inositol phosphates, IP6 most potently stimulates LKB1-only–mediated AMPKα2/β1/γ1 phosphorylation (IP6 > IP5 > IP4 = IP5* > IP3 > 5-IP7). IP5 displays partial stimulatory effect. IP6K1 products IP5* and 5-IP7 are ineffective. Data represent results from duplicate experiments. (E) IP6K1 inhibits IP6-mediated AMPKα2/β11 phosphorylation by LKB1-only, whereas the inactive IP6K1 mutant is much less efficient. Data represent results from 3 independent experiments. (F) 5-IP7 reverses IP6-mediated AMPKα2/β1/γ1 phosphorylation by LKB1-only. Data represent results obtained from 3 independent experiments. (G) IP6 also enhances LKB1-complex–mediated AMPKα2/β11 phosphorylation. Other inositol polyphosphates are ineffective. Data represent results obtained from duplicate experiments. (H) IP6 enhances CaMKKβ-mediated AMPKα21/γ1 phosphorylation. Data represent results obtained from duplicate experiments. (I) IP6 does not enhance LKB1-mediated phosphorylation of heat-denatured AMPKα2/β1/γ1. Data represent results obtained from 3 independent experiments. (J) IP6-mediated enhancement of AMPK phosphorylation is largely similar when AMPKα is used alone or in a complex with AMPKα2/β1/γ1. Data represent results obtained from 3 independent experiments. (K) AMP stimulates LKB1-mediated AMPKα2/β11 phosphorylation at 50- to 100-μM concentrations. Data represent results obtained from duplicate experiments. (L) IP6 or 5-IP7 does not influence active AMPK’s activity on its target SAMStide (n = 3; 1-way ANOVA). Data are expressed as mean ± SEM. §P < 0.0001.