ThermoMouse: An In Vivo Model to Identify Modulators of UCP1 Expression in Brown Adipose Tissue

Abstract

SUMMARY Obesity develops when energy intake chronically exceeds energy expenditure. Because brown adipose tissue (BAT) dissipates energy in the form of heat, increasing energy expenditure by augmenting BAT-mediated thermogenesis may represent an approach to counter obesity and its complications. The ability of BAT to dissipate energy is dependent on expression of mitochondrial protein Uncoupling Protein 1 (UCP1). To facilitate the identification of pharmacological modulators of BAT UCP1 levels, which may have potential as anti-obesity medications, we have developed a transgenic model in which luciferase activity faithfully mimics endogenous UCP1 expression and its response to physiologic stimuli. Phenotypic screening of a library using cells derived from this model yielded a small-molecule that increases UCP1 expression in brown fat cells and mice. Upon adrenergic stimulation, compound-treated mice showed increased energy expenditure. These tools offer an opportunity to identify pharmacologic modulators of UCP1 expression and uncover new regulatory pathways that impact BAT-mediated thermogenesis.

Brown and Beige Fat: Physiological Roles beyond Heat Generation

“…For example, we have recently developed a mouse model, termed ThermoMouse in which luciferase expression is regulated by the Ucp1 gene regulatory elements. A cell based high-throughput screen platform using brown adipocytes from ThermoMouse identified a small compound WWL113 that induces UCP1 expression and whole body energy expenditure in vivo (Galmozzi et al, 2014). This study provides an important proof of concept that targeting UCP1 using small molecules can be a plausible approach for enhancing whole body energy expenditure in vivo .…”

Blocking FSH induces thermogenic adipose tissue and reduces body fat

“…To test whether the Ab reverses Fsh-induced inhibition of Ucp1 , a master regulator of adipocyte beiging and thermogenesis 8, 9 , we used immortalized dedifferentiated brown adipocytes derived from the ThermoMouse (a.k.a. Thermo cells), in which the Ucp1 promoter drives a Luc2-T2A–tdTomato reporter 10 (Extended Data Fig. 1e).…”

Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis

“…A plausible approach is to perform unbiased chemical compound screening to dissect the selective signaling pathways that control brown and/or beige adipocytes. To this end, we have recently developed an in vivo model, ThermoMouse, in which luciferase expression faithfully recapitulates endogenous UCP1 expression (117). This tool provides new opportunities to identify pharmacologic modulators of brown and beige adipocyte development.…”