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 5

Adipocyte-specific Ip6k1 deletion enhances browning.

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Adipocyte-specific Ip6k1 deletion enhances browning. (A) Chronic cold en...
(A) Chronic cold enhances adipose tissue remodeling that resembles browning in CD-AdKOs (image represents data from 3 individual mice per group). (B) Ucp1 and Pgc1 expression levels are higher in AdKOs at 23°C and are further enhanced by chronic cold exposure (n = 6 mice per group; 1-way ANOVA). (C) Chronic cold enhances PGC1-α and UCP1 protein levels in CD-AdKO IWAT and RWAT (n = 3 mice per group). (D) Immunohistochemistry reveals enhanced UCP1 protein levels in chronic-cold-exposed CD-AdKO IWAT and RWAT (images represent results obtained from n = 3 mice per group). (E) Browning and thermogenic and mitochondrial EE machinery are upregulated in chronic-cold-exposed CD-AdKOs (n = 6 mice per group; t test). (F) SVFs (n = 6 mice per preparation) isolated from AdKO IWAT display enhanced beige adipogenesis. Images represent results obtained from at least 3 independent experiments. (G) Beige and mitochondrial activity markers are upregulated in AdKO IWAT beige adipocytes (n = 6 mice per preparation; triplicate samples). (H) OCR is higher in AdKO IWAT beige adipocytes (n = 6 mice per preparation; 10 replicates). OligoM, oligomycin; Anti, antimycin A; rot, rotenone. (I) Quantification of H reveals that average proton leak and maximal respiratory capacity are significantly higher in AdKO IWAT beige adipocytes. Data in all panels are expressed as mean ± SEM. *P < 0.05, **P < 0.01, #P < 0.001, §P < 0.0001.