Editors' ChoiceLIPID METABOLISM

Fat up to BAT

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Science Translational Medicine  04 Jul 2018:
Vol. 10, Issue 448, eaau1972
DOI: 10.1126/scitranslmed.aau1972

Abstract

The mitochondrial lipid cardiolipin is critical for thermogenesis in brown adipocytes, and reduced expression of cardiolipin synthase is associated with markers of type 2 diabetes.

Brown adipose tissue (BAT) is an unconventional fat depot that is not involved in fat storage, but rather in burning various cellular fuels. Upon activation by cold exposure, mitochondria burn lipids and carbohydrates to generate heat as opposed to ATP (adenosine triphosphate) via uncoupled respiration. As such, BAT has emerged as a target to treat cardiometabolic diseases, such as obesity and type 2 diabetes. However, which factors contribute to the full potentiation of the thermogenic response in BAT remain incompletely understood.

Sustarsic and colleagues set out to identify new thermogenic regulators in an unbiased fashion using proteomics on BAT from cold-challenged mice. They found a massive enrichment of proteins involved in fat metabolism. To investigate changes in lipid metabolism when the BAT was exposed to cold temperatures, they analyzed the lipidome in detail. They noticed a striking increase in the amount of cardiolipin, a phospholipid that resides exclusively in the inner mitochondrial membrane.

To probe the causal involvement of cardiolipin in BAT biology, the authors used an elegant set of mouse models in which the cardiolipin synthase gene, Crls1, was selectively ablated in adipose tissues. These mice lost their tolerance to cold and their insulin sensitivity, which was accompanied by abnormal mitochondrial mass, shape, and function. Strikingly, they found a genetic variant in the CRLS1 gene associated with various markers of metabolic disease in the Danish population. What’s more, CRLS1 expression was reduced in the adipose tissue of individuals with type 2 diabetes compared with people with normal glucose tolerance.

Altogether, the work described here identifies the mitochondrial lipid cardiolipin as a critical factor in adipose tissue thermogenesis and whole-body energy homeostasis. The genetic association between CRLS1 and metabolic disease in humans suggests that this process could be amenable to treatment, but future work will have to establish how this pathway can be targeted.

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