Uncoupling protein-1 expression does not protect mice from diet-induced obesity

Abstract

We studied the metabolic phenotype of a novel Ucp1-LUC-iRFP713 knock-in reporter gene mouse model originally generated to monitor endogenous Ucp1 gene expression. Both reporter mice and reporter cells reliably reflected Ucp1 gene expression in vivo and in vitro. We here report an unexpected reduction in UCP1 content in homozygous knock-in (KI) reporter mice. As a result, the thermogenic capacity of KI mice stimulated by norepinephrine was largely blunted, making them more sensitive to an acute cold exposure. In return, these reporter mice with reduced UCP1 expression enabled us to investigate the physiological role of UCP1 in the prevention of weight gain. We observed no substantial differences in body mass across the three genotypes, irrespective of the type of diet or the ambient temperature, possibly due to the insufficient UCP1 activation. Indeed, activation of UCP1 by daily injection of the selective β3-adrenergic receptor agonist CL316,243 resulted in significantly greater reduction of body weight in WT mice than in KI mice. Taken together, we conclude that the intact expression of UCP1 is essential for cold-induced thermogenesis but the presence of UCP1 per se does not protect mice from diet-induced obesity.

Uncoupling Protein 1 Does Not Produce Heat without Activation

“…The most important and stringent model for robust validation of the metabolic functions of UCP1 is the UCP1 knockout (KO) mouse. This model has varyingly been reported to be either protected from diet-induced obesity [ 52 , 54 , 55 , 56 , 57 ] or not [ 6 , 58 , 59 , 60 , 61 , 62 , 63 ] at thermoneutral conditions. The reason for this confusing pattern of varying outcome—even between cohorts of the same colony [ 64 ]—is currently unknown.…”

“…While this may appear beneficial in the context of widespread metabolic disease today, it most certainly acted as a constraint during evolutionary time spans of food scarcity, rendering UCP1 inherently inactive when not explicitly required and activated and tightly controlled by multiple regulatory layers, including the transcriptional level, mRNA stability and protein degradation, ensuring cell specificity and temporal control. Consequently, simply increasing BAT mass or UCP1 abundance does not lead to an increase in thermogenesis without a concomitant increase or at least maintenance of the sympathetic nervous system (SNS) tone within BAT or alternative activating stimuli [ 6 , 7 ]. Thus, genetic or pharmacological manipulations that promote increases in BAT mass in humans or animal models, in and of themselves, will not guarantee increased thermogenesis and consequent metabolic benefit.…”

“…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).…”

Susceptibility to diet induced obesity at thermoneutral conditions is independent of UCP1

“…One explanation for the increased susceptibility to DIO in UCP1-KO mice may be adaptations in metabolism, leading to a more efficient metabolism or the lack of diet-induced thermogenesis in UCP1-KO mice (von Essen et al 2017). However, recent data from a UCP1 knockdown model (H. Wang et al 2021) demonstrate that UCP1 abundance alone does not protect against DIO at thermoneutrality. Despite having remarkable reduced but still activatable UCP1 levels, these mice are not more or less prone to DIO compared to wildtype littermates with normal functional levels of UCP1.…”

Susceptibility to diet-induced obesity at thermoneutral conditions is independent of UCP1

“…One explanation for the increased susceptibility to DIO in UCP1-KO mice may be increased metabolic efficiency, defined as a larger gain of body fat mass per unit of metabolizable energy, due to the lack of diet-induced BAT thermogenesis in UCP1-KO mice (31). However, recent data from a UCP1 knockdown model (34) demonstrate that UCP1 abundance alone does not protect against DIO at thermoneutrality. Despite having remarkable reduced but still inducable UCP1 expression levels, these mice are not more or less prone to DIO compared with wild-type (WT) littermates with high-fat diet-induced elevation in UCP1 expression.…”