Beige Fat Maintenance; Toward a Sustained Metabolic Health

Abstract

Understanding the mammalian energy balance can pave the way for future therapeutics that enhance energy expenditure as an anti-obesity and anti-diabetic strategy. Several studies showed that brown adipose tissue activity increases daily energy expenditure. However, the size and activity of brown adipose tissue is reduced in individuals with obesity and type two diabetes. Humans have an abundance of functionally similar beige adipocytes that have the potential to contribute to increased energy expenditure. This makes beige adipocytes a promising target for metabolic disease therapies. While brown adipocytes tend to be stable, beige adipocytes have a high level of plasticity that allows for the rapid and dynamic induction of thermogenesis by external stimuli such as low environmental temperatures. This means that after browning stimuli have been withdrawn beige adipocytes quickly transition back to their white adipose state. The detailed molecular mechanisms regulating beige adipocytes development, function, and reversibility are not fully understood. The goal of this review is to give a comprehensive overview of beige fat development and origins, along with the transcriptional and epigenetic programs that lead to beige fat formation, and subsequent thermogenesis in humans. An improved understanding of the molecular pathways of beige adipocyte plasticity will enable us to selectively manipulate beige cells to induce and maintain their thermogenic output thus improving the whole-body energy homeostasis.

Keywords: beige fat; brown fat; browning; development and origin; epigenetic regulation; maintenance; thermogenesis; transcriptional regulation.

Figure 1

Bidirectional transition between beige and white adipocytes; the beige-to-white transition (browning) has been extensively studied at the levels of (A) transcriptional and epigenetic regulation including the chromatin landscape, transcriptional regulators, and epigenetic modifiers, (B) the role of lifestyle and environment including diet, fasting, obesity, exercise, temperature, and circadian rhythm, (C) the role of endocrine factors and hormones secreted by various organs including pancreas, muscle, liver, heart, gut, and fat when adapting to environmental challenges, (D) the role of natural products and plant extracts as well as the role of synthetic chemical products including small molecules, nanoparticles, synthetic peptides, and drug. Contrarily, the beige-to-white transition which is the immediate result of stimuli removal is poorly investigated and so far, (E) mitochondrial disappearance (mitophagy) is known to be the main contributor. Figure created with ©BioRender.io.