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 9

IP6K1 regulation of adipose tissue metabolism modulates whole-body energy homeostasis.

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IP6K1 regulation of adipose tissue metabolism modulates whole-body energ...
Left panel: Adipocyte-specific IP6K1 regulates energy metabolism by inhibiting the AMPK pathway via a novel mechanism. IP6 enhances upstream kinase-mediated AMPK stimulatory phosphorylation. IP6K1, on the other hand, inhibits AMPK phosphorylation by generating 5-IP7 from IP6. AMPK activates the transcriptional co-activator PGC1α, which is a major regulator of adipose tissue browning and UCP1 mediated thermogenic EE. Moreover, IP6K1 generated 5-IP7 inhibits Akt. IP6K1 also reduces serum levels of ADIPOQ, which indirectly influences these pathways. Thus, adipocyte-specific IP6K1 promotes DIO and insulin resistance. Right panel: In AdKO mice, Akt, AMPK, and ADIPOQ signaling is upregulated, which leads to thermogenic EE mediated by adipose tissue browning and to global insulin sensitivity. As a result, AdKO mice are protected against HFD-induced weight gain and insulin resistance. Thus, adipocyte-specific IP6K1 is a major regulator of global energy metabolism. Striped and bold encircling arrows indicate reduced and increased effects of AMPK and Akt on tissue metabolism, in the presence and absence of IP6K1, respectively. Thin and thick straight arrows indicate less and more active pathways, respectively.