Ectopic UCP1 Overexpression in White Adipose Tissue Improves Insulin Sensitivity in Lou/C Rats, a Model of Obesity Resistance

Abstract

Brown adipose tissue (BAT), characterized by the presence of uncoupling protein 1 (UCP1), has been described as metabolically active in humans. Lou/C rats, originating from the Wistar strain, are resistant to obesity. We previously demonstrated that Lou/C animals express UCP1 in beige adipocytes in inguinal white adipose tissue (iWAT), suggesting a role of this protein in processes such as the control of body weight and the observed improved insulin sensitivity. A β3 adrenergic agonist was administered for 2 weeks in Wistar and Lou/C rats to activate UCP1 and delineate its metabolic impact. The treatment brought about decreases in fat mass and improvements in insulin sensitivity in both groups. In BAT, UCP1 expression increased similarly in response to the treatment in the two groups. However, the intervention induced the appearance of beige cells in iWAT, associated with a marked increase in UCP1 expression, in Lou/C rats only. This increase was correlated with a markedly enhanced glucose uptake measured during euglycemic-hyperinsulinemic clamps, suggesting a role of beige cells in this process. Activation of UCP1 in ectopic tissues, such as beige cells in iWAT, may be an interesting therapeutic approach to prevent body weight gain, decrease fat mass, and improve insulin sensitivity.

Repurposing beta3-adrenergic receptor agonists for Alzheimer’s disease: Beneficial effects on recognition memory and amyloid pathology in a mouse model

“…Higher levels of UCP1 and Complex I in the BAT detected here indicate a sustained effect of CL-316,243 on BAT thermogenesis after a onemonth chronic treatment in old mice. This is consistent with strong previous evidence that β3AR stimulation leads to increased thermogenic activity of BAT in young mice (Labbé et al, 2016;Poher et al, 2015;Xiao et al, 2015) and humans as well (Cypess et al, 2015;Loh et al, 2018). It also shows that chronic β3AR administration does not induce significant receptor desensitization, despite decreased levels of BAT β3AR following treatment, in agreement with previous works (Nedergaard and Cannon, 2013).…”

“…Since CL-316,243 is well known to improve thermogenesis capacity in mice (Labbé et al, 2016;Poher et al, 2015;Xiao et al, 2015), we then verified whether it was also effective in old NonTg and 3xTg-AD mice. First, interscapular BAT weight was slightly lower in 3xTg-AD compared to NonTg mice, but was not affected by the treatment (Fig.…”

Tumor Cell “Slimming” Regulates Tumor Progression through PLCL1/UCP1‐Mediated Lipid Browning

“…[41] Previous studies have shown that UCP1 ablation can induce the occurrence of obesity and that upregulation of UCP1 can make it easier for the body to consume lipids under the same conditions to achieve the weight loss. [24,42,43] Therefore, losing weight through lipid browning is a way to change the balance point of lipid metabolism, which can enable the body to achieve a new lipid metabolism balance in the direction of slimming rather than just improving lipid consumption. [44] Since obesity is so similar to ccRCC, this phenomenon might also exist in ccRCC.…”

“…[22,23] Lipid browning could destroy energy homeostasis to consume lipids without producing ATP energy, and UCP1 is the most important marker of lipid browning. [24] Immunofluorescence analysis and western blot showed that UCP1 was upregulated in cells stably overexpressing PLCL1 ( Figure 2E; Figure 3E,F, Supporting Information), suggesting that lipid browning might take place in these cells. PLCL1 may promote tumor cell "slimming" by activating a reaction similar to lipid browning.…”

Piperine regulates UCP1 through the AMPK pathway by generating intracellular lactate production in muscle cells

“…It is chiefly expressed in brown adipose tissue, where it regulates thermogenesis and energy expenditure while also protecting against oxidative stress20. Lactate is also known to control UCP1 expression by inducing browning in human and murine white adipocytes, and UCP1 overexpression improves insulin sensitivity in obesity-resistant rats4647. Previous work with rat muscle demonstrated that lactate can drive mitochondrial gene expression and promote fatty acid oxidation, mitochondrial activity, and expression of UCP145.…”