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Futile lipid cycling: from biochemistry to physiology

Nature Metabolism (2024)Cite this article

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Abstract

In the healthy state, the fat stored in our body isn’t just inert. Rather, it is dynamically mobilized to maintain an adequate concentration of fatty acids (FAs) in our bloodstream. Our body tends to produce excess FAs to ensure that the FA availability is not limiting. The surplus FAs are actively re-esterified into glycerides, initiating a cycle of breakdown and resynthesis of glycerides. This cycle consumes energy without generating a new product and is commonly referred to as the ‘futile lipid cycle’ or the glyceride/FA cycle. Contrary to the notion that it’s a wasteful process, it turns out this cycle is crucial for systemic metabolic homeostasis. It acts as a control point in intra-adipocyte and inter-organ cross-talk, a metabolic rheostat, an energy sensor and a lipid diversifying mechanism. In this Review, we discuss the metabolic regulation and physiological implications of the glyceride/FA cycle and its mechanistic underpinnings.

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Fig. 1: Multifaceted regulation of the glyceride/FA cycle.
Fig. 2: Spatial diversity of the glyceride/FA cycle.
Fig. 3: A model of stochastic fate determination of FAs.
Fig. 4: Putative functions of the glyceride/FA cycle.
Fig. 5: Pharmacological modulation of futile lipid cycle and its implications in systemic health.

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Acknowledgements

We express our appreciation for many excellent studies that contributed to concept refining, but we could not cite them due to space limitations. We thank R. S. Dewal for very helpful inputs on content and presentation. We also thank M. Geiger and S. Turner for excellent management support. A.K.S. is grateful to previous mentors Y. Sharma and A. Prakash. Figures were created using BioRender.com.

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  1. Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland

    Anand Kumar Sharma, Radhika Khandelwal & Christian Wolfrum

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Conceptualization: A.K.S.; idea/content refinement: A.K.S., R.K. and C.W.; manuscript writing (first draft): A.K.S.; manuscript editing: A.K.S., R.K. and C.W.; figures were prepared by A.K.S.; funds, administration and supervision: C.W.

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Sharma, A.K., Khandelwal, R. & Wolfrum, C. Futile lipid cycling: from biochemistry to physiology. Nat Metab (2024). https://doi.org/10.1038/s42255-024-01003-0

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