Mitochondrial reactive oxygen species and adipose tissue thermogenesis: Bridging physiology and mechanisms

Abstract

Brown and beige adipose tissues can catabolize stored energy to generate heat, relying on the principal effector of thermogenesis: uncoupling protein 1 (UCP1). This unique capability could be leveraged as a therapy for metabolic disease. Numerous animal and cellular models have now demonstrated that mitochondrial reactive oxygen species (ROS) signal to support adipocyte thermogenic identity and function. Herein, we contextualize these findings within the established principles of redox signaling and mechanistic studies of UCP1 function. We provide a framework for understanding the role of mitochondrial ROS signaling in thermogenesis together with testable hypotheses for understanding mechanisms and developing therapies.

Keywords: adipocyte; adipose tissue; adipose tissue metabolism; mitochondria; reactive oxygen species (ROS); thermogenesis.

Figure 1.

Summary of ROS and thiol redox processes linked to adipocyte thermogenesis. Stimulation of β-adrenergic receptors (β-AR) triggers lipolysis and increased mitochondrial ROS levels through a still uncharacterized mechanism. Elevated mitochondrial ROS and oxidation of thiol status by acute adrenergic stimulus or genetic modification support elevated thermogenic respiration as well as transcriptional activation of genes required to maintain thermogenesis. In contrast, pharmacological inhibition of these processes dampens ROS-dependent thermogenic signaling. Determining functional targets of thermogenic ROS signaling is an area of active investigation, including a recently described redox-sensitive site on UCP1 that alters sensitivity to leak respiration upon adrenergic stimulus. Red parameters, pro-thermogenic manipulations; green, anti-thermogenic manipulations; NE, norepenephrine; CL, CL-316 243; LCFA, long chain fatty acids; GCLM, glutamate–cysteine ligase modifier subunit.