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 6

IP6K1 reduces AMPK-mediated adipocyte browning.

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IP6K1 reduces AMPK-mediated adipocyte browning. (A) AMPK stimulatory pho...
(A) AMPK stimulatory phosphorylation (T172) and its activity are enhanced in WT mice following acute cold exposure (n = 4–5 mice per group). (B) AMPK phosphorylation is dramatically augmented in acute-cold-exposed AdKOs (n = 3 mice per group). (C) AMPK activity is higher in 2 separate preparations (n = 6 mice per preparation) of AdKO beige adipocytes differentiated from IWAT SVF in vitro. (D) siRNA-mediated AMPKα depletion substantially reduces AMPKα protein level in LoxP and AdKO beige adipocytes. Moreover, PGC1-α and UCP1 protein levels, which are higher in AdKO adipocytes, are reduced following AMPKα depletion. Data represent results obtained from 2 independent experiments. (E) Ucp1 mRNA expression is slightly reduced by AMPKα siRNA treatment in LoxP mice. Conversely, Ucp1 expression, which is significantly higher in AdKO adipocytes compared with LoxPs, is substantially reduced following AMPKα depletion. Data represent results obtained from 5 experimental replicates. (F) AdKO beige adipocytes express higher levels of Ucp1 compared with LoxP adipocytes under basal conditions (control). TNP (5 μM, 16 hours) substantially enhances Ucp1 expression in LoxP adipocytes, whereas it does not influence Ucp1 in AdKO adipocytes. The AMPK activator AICAR enhances Ucp1 expression to a higher extent in LoxP adipocytes. Data represent results obtained from 5 experimental replicates. (G) TNP (5 μM) enhances AMPK phosphorylation and activity in beige adipocytes differentiated in vitro from isolated from WT IWAT SVF. Immunoblot represents results from at least 3 independent experiments. (H and I) A single dose of TNP (20 mg/kg body weight; i.p.) enhances AMPK phosphorylation and activity on ACC in the IWAT of HFD-fed mice (n = 3 mice per group; t test). Data in all panels are expressed as mean ± SEM. *P < 0.05, **P < 0.01.