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Uncoupling protein 1 (UCP1) plays a key role in nonshivering thermogenesis and is involved in the pathogenesis of obesity. In a previous study, we generated adipocyte-specific UCP1 knock-in (UCP1 -KI) pigs, which exhibited improved thermoregulatory ability and decreased fat deposition. To investigate whether UCP1 knock-in alters the lipid composition of adipose tissues, lipidomics of inguinal subcutaneous white adipose tissue (iWAT) and backfat from 6-month-old cold-treated UCP1 -KI pigs and wild-type (WT) pigs were profiled. In addition, genome-wide RNA-sequencing of iWAT was performed to further study the genetic basis for lipid alterations. The results showed that iWAT and backfat from UCP1- KI pigs exhibited distinct lipidomic profiles, as the mild lipid alteration was observed in backfat of UCP1 knock-in pigs. Inguinal WAT from UCP1 -KI pigs contained significantly decreased total triacylglycerol (p < 0.05), together with the downregulation of genes involved in fatty acid metabolism, suggesting the decreased lipogenesis in iWAT of UCP1 -KI pigs. Significantly increased levels of total sphingolipids (p <0.05) were also observed in iWAT from UCP1 -KI pigs. Notably, two mitochondrial-specific lipid species, cardiolipin CL72:8 (18:2) and CL74:9 (18:2), were found to be dramatically increased in iWAT from UCP1 -KI pigs, suggesting enhanced mitochondrial function. This observation was further supported by the significant upregulation of numerous mitochondrial-related genes and significantly increased number of large mitochondria and mitochondrial cristae in iWAT of UCP1 -KI pigs. Taken together, these data illustrate the specific role of UCP1 in lipid metabolism of fat tissues in pigs and provide new data for characterization of fat traits in UCP1 -KI pigs. • Inguinal subcutaneous white adipose tissue (iWAT) and backfat from UCP1- KI pigs exhibited distinct lipidomic profiles. • Significant reductions of total TAG in iWAT from UCP1 -KI pigs, together with the significantly downregulated fatty acid metabolism related genes, indicate the decreased lipid synthesis in iWAT of UCP1 -KI pigs. • Mitochondrial function was enhanced in iWAT of UCP1 -KI pigs, as evidenced by the significantly increased cardiolipin levels, upregulated numerous mitochondrial genes, increased number of large mitochondria and mitochondrial cristae density. [ABSTRACT FROM AUTHOR]

Background: C1q/tumor necrosis factor-related protein 1 (CTRP1) is an adipokine secreted by adipose tissue, related to chondrocyte proliferation, inflammation, and glucose homeostasis. However, the therapeutic effects on metabolic disorders and the underlying mechanism were unclear. Here, we investigated the functions and mechanisms of CTRP1 in treating obesity and diabetes.Methods: The plasmid containing human CTRP1 was delivered to mice by hydrodynamic injection, which sustained expression of CTRP1 in the liver and high protein level in the blood. High-fat diet (HFD) fed mice and STZ-induced diabetes model were used to study the effects of CTRP1 on obesity, glucose homeostasis, insulin resistance, and hepatic lipid accumulation. The lipid accumulation in liver and adipose tissue, glucose tolerance, insulin sensitivity, food intake, and energy expenditure were detected by H&E staining, Oil-Red O staining, glucose tolerance test, insulin tolerance test, and metabolic cage, respectively. The metabolic-related genes and signal pathways were determined using qPCR and western blotting.Results: With high blood circulation, CTRP1 prevented obesity, hyperglycemia, insulin resistance, and fatty liver in HFD-fed mice. CTRP1 also improved glucose metabolism and insulin resistance in obese and STZ-induced diabetic mice. The metabolic cage study revealed that CTRP1 reduced food intake and enhanced energy expenditure. The mechanistic study demonstrated that CTRP1 upregulated the protein level of leptin in blood, thermogenic gene expression in brown adipose tissue, and the gene expression responsible for lipolysis and glycolysis in white adipose tissue (WAT). CTRP1 also downregulated the expression of inflammatory genes in WAT. Overexpression of CTRP1 activated AMPK and PI3K/Akt signaling pathways and inhibited ERK signaling pathway.Conclusion: These results demonstrate that CTRP1 could improve glucose homeostasis and prevent HFD-induced obesity and fatty liver through upregulating the energy expenditure and reducing food intake, suggesting CTRP1 may serve as a promising target for treating metabolic diseases. [ABSTRACT FROM AUTHOR]

Beige adipose tissue has been considered to have potential applications in combating obesity and its related metabolic diseases. However, the mechanisms of acute cold-stimulated beige formation still remain largely unknown. Here, transcriptional analysis of acute cold-stimulated (4 °C for 4 h) subcutaneous white adipose tissue (sWAT) was conducted to determine the molecular signatures that might be involved in beige formation. Histological analysis confirmed the appearance of beige adipocytes in acute cold-treated sWAT. The RNA-sequencing data revealed that 714 genes were differentially expressed (p-value < 0.05 and fold change > 2), in which 221 genes were upregulated and 493 genes were downregulated. Gene Ontology (GO) analyses showed that the upregulated genes were enriched in the GO terms related to lipid metabolic process, fatty acid metabolic process, lipid oxidation, fatty acid oxidation, etc. In contrast, downregulated genes were assigned the GO terms of regulation of immune response, regulation of response to stimulus, defense response, etc. The expressions of some browning candidate genes were validated in cold-treated sWAT and 3T3-L1 cell browning differentiation. In summary, our results illustrated the transcriptional response of sWAT to acute cold exposure and identified the genes, including Acad11, Cyp2e1, Plin5, and Pdk2, involved in beige adipocyte formation in mice. [ABSTRACT FROM AUTHOR]