White Adipose Tissue Browning: A Double-edged Sword

Abstract

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.

Keywords: ER stress; burns; cancer; hypermetabolism; uncoupling protein 1; white adipose tissue.

Figure 1. Hypermetabolic response to burn injury

Burn injury results in a number of pathological alterations in various tissues of the body. Alterations in the metabolic tissues of liver, adipose, and skeletal muscle are illustrated post-burn injury. Abnormalities in the function of these metabolic tissues ultimately affect other organs like the skin and impair wound healing.

Figure 2. Characteristics and properties of the different adipose tissue depots

Immunohistochemistry micrographs illustrating the morphology and properties of human and mouse adipose tissue depots. (A) Left, human WAT (acquired from subcutaneous abdominal depot) have uni-occular morphology, contain very little mitochondria, and do not express UCP-1. Middle, browning of WAT (induced by burn injury in the image illustrated) leads to the formation of a multi-occular, mitochondria-rich, and UCP-1-expressing beige/brite adipocytes. Right, human brown adipocytes (acquired from the supraclavicular region of a burn patient) are characterized by a multi-occular morphology, high mitochondrial content, and increased UCP-1 expression. (B) Left, mouse WAT (acquired from inguinal depot) also has uni-occular morphology, contains very little mitochondria, and does not express UCP-1. Middle, browning of inguinal WAT (induced by burn injury) leads to the formation of a multi-occular, mitochondria-rich, and UCP-1 expressing beige/brite adipocytes. Right, mouse BAT (acquired from interescapular region) showing multi-occular morphology, high mitochondrial content, and increased UCP-1 expression.

Figure 3. WAT browning mediated metabolic dysfunction

During WAT browning, substantial metabolic alterations take place in patients with hypermetabolic conditions (burns, cancer, and heart disease). Left WAT browning enhances whole body energy expenditure causing a catabolic state of muscle protein breakdown and increased lipolysis, ultimately leading to cachexia; a debilitating condition characterized by muscle and adipose wasting. Middle: WAT browning activates lipolysis and increases serum cholesterol levels, ultimately leading to atherosclerosis; a condition characterized by plaque growth and instability in the heart. Right: WAT browning stimulates lipolysis and FFA efflux ultimately leading to hepatic steatosis; a condition characterized by ectopic fat accumulation and liver failure. Full arrows indicate well-substantiated findings; whereas dashed arrows indicate less characterized findings.

Figure 4. Hepatic ER stress response to burn injury

A schematic diagram illustrating the acute response to burn injury, in which there is increased MAM formation in the liver. Increased MAM formation drives higher Ca²⁺ transfer from ER (via IP3R1) to the mitochondria, leading to Ca²⁺ overload. This excessive uncontrolled influx of Ca²⁺ into the mitochondria leads to mitochondrial dysfunction via impairments in oxidative capacity and swelling. The release of cytochrome C from the mitochondria also sustains chronic ER stress via the phosphorylation of the IP3R receptors to release more calcium, ultimately resulting in cellular apoptosis.