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

Abstract

Objective Activation of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) upon cold stimulation leads to substantial increase in energy expenditure to defend body temperature. Increases in energy expenditure after a high caloric food intake, termed diet-induced thermogenesis, are also attributed to BAT. These properties render BAT a potential target to combat diet-induced obesity. However, studies investigating the role of UCP1 to protect against diet-induced obesity are controversial and rely on the phenotyping of a single constitutive UCP1-knockout model. To address this issue, we generated a novel UCP1-knockout model by Cre-mediated deletion of Exon 2 in the UCP1 gene. We studied the effect of constitutive UCP1 knockout on metabolism and the development of diet-induced obesity. Methods UCP1 knockout and wildtype mice were housed at 30°C and fed a control diet for 4-weeks followed by 8-weeks of high-fat diet. Body weight and food intake were monitored continuously over the course of the study and indirect calorimetry was used to determine energy expenditure during both feeding periods. Results Based on Western blot analysis, thermal imaging and noradrenaline test, we confirmed the lack of functional UCP1 in knockout mice. However, body weight gain, food intake and energy expenditure were not affected by deletion of UCP1 gene function during both feeding periods. Conclusion We introduce a novel UCP1-KO mouse enabling the generation of conditional UCP1-knockout mice to scrutinize the contribution of UCP1 to energy metabolism in different cell types or life stages. Our results demonstrate that UCP1 does not protect against diet-induced obesity at thermoneutrality.

Loss of UCP1 function augments recruitment of futile lipid cycling for thermogenesis in murine brown fat

“…WT and UCP1KO mice on a C57BL/6N background were generated as described previously [ 35 ]. All animals were bred in a specific pathogen-free facility under controlled housing conditions (55% relative humidity, 23 °C ambient temperature, 12 h/12 h light dark cycle) and had ad libitum access to food and water.…”

Obesity-resistance of UCP1-deficient mice associates with sustained FGF21 sensitivity in inguinal adipose tissue

“…Endogenous FGF21 fully mediates obesity resistance in mice with genetic inactivation of the adipose-specific mitochondrial uncoupling protein 1 (UCP1), when fed high fat diets (HFD) at room temperature (representing mild cold conditions) ( 32 ). The phenomenon of increased FGF21 levels and resistance to diet induced obesity in UCP1 KO mice is only seen at mild cold, not thermoneutral conditions ( 33 , 34 ). To date, the underlying mechanisms how FGF21 counteracts obesity are not understood but associate with the browning of WAT.…”

Uncoupling Protein 1 Does Not Produce Heat without Activation

“…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.…”

“…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.…”