Uncoupling Protein 1 Does Not Produce Heat without Activation

Figures

• 

  Figure 1. Brown fat thermogenesis is dynamic, fine-tuned and highly sensitive to changes in ambient temperature. It can be fully activated by cold exposure or norepinephrine treatment, is less active when temperature rises and even repressed when ambient temperature reaches the themoneutral zone. As such, activation of brown fat by adrenergic activation can reveal maximal thermogenic capacity, not actual thermogenic state. Moreover, actual thermogenesis is tightly regulated and subject to feedback regulation. Non-brown fat-mediated heat production, such as synthetic uncoupler and peripheral hyperthyroidism, can leave thermogenic brown and beige fat metabolically reduced or even inactive.

• 

  Figure 2. Physiological and molecular brakes of brown fat activation and their release. In accordance with the needs of thermal balance, brown fat thermogenic power is necessarily tightly controlled and subject to synergistic feedback mechanisms. Thermogenesis is highly sensitive to many physiological factors, such as environmental temperature (1), energy state (2), endogenous heat production (3), heat loss (4), body mass (5) as well as social behavior, such as huddling (6). At the tissue and molecular level, the complex thermogenic microenvironment and molecular networks constraining brown fat activity include nerve (7) and vascular (8) rarefaction, norepinephrine clearance (9), paracrine/endocrine Gi-mediated GPCR signaling (10), intracellular cAMP degradation (11), PKA activity fine-tuning (12), phosphatase (PP)-mediated dephosphorylation of phosphoprotein (13) and purine nucleotide metabolism remodeling (14). These built-in brake systems efficiently titrate the local adaptation required to accurately meet constantly varying thermogenic demands.