Review
White Adipose Tissue Browning: A Double-edged Sword

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Trends

Inducing ‘browning’ within white adipose tissue (WAT), that is, by increasing uncoupling protein 1 (UCP-1) expression, has attracted much interest in the field of obesity.

WAT browning has several beneficial metabolic effects such as increasing energy expenditure and reducing adiposity.

The unique metabolic benefits of browning in WAT have recently been overshadowed by its implication in cachexia, atherosclerosis, and hepatic steatosis during hypermetabolic conditions.

WAT browning appears to be a double-edged sword, beneficial in obesity and diabetes, but detrimental in hypermetabolic conditions.

Understanding the molecular mechanisms underlying browning-induced hypermetabolism may allow for the development of therapeutic approaches that attenuate or even eliminate the associated adverse metabolic effects.

The study of white adipose tissue (WAT) ‘browning’ has become a ‘hot topic’ in various acute and chronic metabolic conditions, based on the idea that WAT browning might be able to facilitate weight loss and improve metabolic health. However, this view cannot be translated into all areas of medicine. Recent studies identified effects of browning associated with adverse outcomes, and as more studies are being conducted, a very different picture has emerged about WAT browning and its detrimental effect in acute and chronic hypermetabolic conditions. Therefore, the notion that browning is supposedly beneficial may be inadequate. In this review we analyze how and why browning in chronic hypermetabolic associated diseases can be detrimental and lead to adverse outcomes.

Section snippets

Hypermetabolism in Response to Injury

The hypermetabolic response (see Glossary) is characterized by a profound increase in the release of free fatty acids (FFAs) and glycerol from fat, glucose production by the liver, and amino acids from muscle, ultimately resulting in significant elevations in resting energy expenditure 1, 2, 3. Catecholamines, corticosteroids, and inflammatory cytokines have been implicated as the primary mediators of this hypermetabolic response 2, 4. Although this phenomenon may be viewed as an adaptive

Browning of WAT in Hypermetabolic Conditions

Reports of browning in traditionally white adipose depots occurred decades ago, when it was observed that mice acclimated to cold developed brown adipose tissue (BAT) characteristics, that is, small multiocular cells enriched in mitochondria, in a subset of cells in the parametrial adipose depots 10, 11. With regards to humans, there is a dearth of literature concerning the browning of WAT. However, three new studies have recently discovered WAT browning in the development and progression of

Is the Browning of WAT Good or Bad During Hypermetabolism?

Logically, it would not seem beneficial to activate heat production and intense nutrient utilization under conditions of hypermetabolism like those seen in burns, massive trauma, and cancer. While for some aspects of this question the answers are straightforward; this biological occurrence under pathological conditions has remained a mystery. Here we consider how WAT browning is deleterious in the context of hypermetabolic conditions such as burns and cancer (Figure 3, Key Figure).

Catecholamines

In burns, marked increases in catecholamines have been noted in patients years after the initial injury [4]. This sustained catecholamine surge in burns has recently been shown to initiate WAT browning and the cascade of events leading to the hypermetabolic response 13, 14. It has long been assumed that the adrenal glands were the only source of catecholamine secretion, however, this has recently changed with the discovery that macrophages can secrete catecholamines as well. In this study it

Mechanisms of Metabolic Dysfunction During Hypermetabolism: Lipotoxicity and the Browning of WAT

Here, we focus on the by-product of WAT browning, namely the excessive release of lipids that ultimately causes tissue dysfunction. Specifically, we consider the lipid profile (both good and bad) in hypermetabolic patients, and its mechanisms of action in causing hepatic and adipose tissue dysfunction, as well as inflammation.

Concluding Remarks and Future Perspectives

We have highlighted just a few of the questions that have been sparked by recent findings that revealed WAT browning may be detrimental for burn and cancer patients. The aim of this review was to stimulate debate and research, and to address an area of WAT browning that has largely been ignored. For instance, we have illustrated how the browning process and its byproduct lead to a number of alterations in hepatocytes, adipocytes, and immune cells. Ultimately, these alterations facilitate and

Acknowledgments

A.A. is a Vanier Scholar and a recipient of the Vanier Canada Graduate Scholarship. M.G.J. holds grants from Canadian Institutes of Health Research, Canada Fund for Innovation (CFI) Leader's Opportunity Fund Project, and the National Institutes of Health.

Glossary

Atherosclerosis
A condition characterized by the deposition of plaques of fatty material on the inner walls of the arteries.
Autophagy
An intracellular recycling program, whereby organelles, cytoplasmic proteins, protein aggregates, and lipids are delivered to lysosomes for catabolic breakdown to be reused by the cell for energy and macromolecular synthesis.
Beige/Brite Adipose Tissue
UCP1-positive adipocytes appearing predominantly in white adipose tissue (WAT) in response to cold, injury (thermal

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