Elsevier

Molecular Metabolism

Volume 6, Issue 1, January 2017, Pages 73-85
Molecular Metabolism

Original Article
Global IP6K1 deletion enhances temperature modulated energy expenditure which reduces carbohydrate and fat induced weight gain

https://doi.org/10.1016/j.molmet.2016.11.010Get rights and content
Under a Creative Commons license
open access

Highlights

  • Global IP6K1 deletion protects mice from DIO and insulin resistance, irrespective of environmental temperature conditions.

  • Chow diet-fed IP6K1-KO mice expend more energy at 5 °C.

  • High fat diet-fed IP6K1-KO mice oxidize more carbohydrate at 5 °C; whereas they oxidize more fat at 23 °C and 30 °C.

  • Enhanced expression of UCP1, but not other EE markers, is partly impaired in high fat diet-fed IP6K1-KO mice at 30 °C.

  • IP6K1 promotes cellular fat accumulation by diminishing AMPK mediated energy metabolism.

Abstract

Objective

IP6 kinases (IP6Ks) regulate cell metabolism and survival. Mice with global (IP6K1-KO) or adipocyte-specific (AdKO) deletion of IP6K1 are protected from diet induced obesity (DIO) at ambient (23 °C) temperature. AdKO mice are lean primarily due to increased AMPK mediated thermogenic energy expenditure (EE). Thus, at thermoneutral (30 °C) temperature, high fat diet (HFD)-fed AdKO mice expend energy and gain body weight, similar to control mice. IP6K1 is ubiquitously expressed; thus, it is critical to determine to what extent the lean phenotype of global IP6K1-KO mice depends on environmental temperature. Furthermore, it is not known whether IP6K1 regulates AMPK mediated EE in cells, which do not express UCP1.

Methods

Q-NMR, GTT, food intake, EE, QRT-PCR, histology, mitochondrial oxygen consumption rate (OCR), fatty acid metabolism assays, and immunoblot studies were conducted in IP6K1-KO and WT mice or cells.

Results

Global IP6K1 deletion mediated enhancement in EE is impaired albeit not abolished at 30 °C. As a result, IP6K1-KO mice are protected from DIO, insulin resistance, and fatty liver even at 30 °C. Like AdKO, IP6K1-KO mice display enhanced adipose tissue browning. However, unlike AdKO mice, thermoneutrality only partly abolishes browning in IP6K1-KO mice. Cold (5 °C) exposure enhances carbohydrate expenditure, whereas 23 °C and 30 °C promote fat oxidation in HFD-KO mice. Furthermore, IP6K1 deletion diminishes cellular fat accumulation via activation of the AMPK signaling pathway.

Conclusions

Global deletion of IP6K1 ameliorates obesity and insulin resistance irrespective of the environmental temperature conditions, which strengthens its validity as an anti-obesity target.

Keywords

IP6K
Obesity
Diabetes
Energy expenditure
β-oxidation

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