[This retracts the article DOI: 10.1155/2014/439146.].

[This corrects the article DOI: 10.1155/2016/7175067.].

Obesity is driven by chronic energy imbalance and is associated with multiple metabolic diseases. As adipocyte thermogenesis contributes to energy expenditure, it is being actively investigated as a possible target for obesity treatment. This review summarizes recent progress in the molecular regulation of adipocyte thermogenesis, focusing mainly on preclinical mechanistic evidence from cellular and animal studies, while discussing clinical and human data only where available. We review emerging regulators within the cAMP pathway, the PRDM16-PPARγ axis, and mitochondrial quality control and metabolism, together with other pathways that modulate brown and beige adipocyte function. We also discuss their metabolic effects in experimental obesity settings. Nevertheless, the therapeutic relevance of these findings remains uncertain because much of the evidence is still preclinical, and because translation is complicated by species differences, adipose depot heterogeneity, and the limited number of validated human studies. This review therefore offers an updated synthesis of recent mechanistic advances while emphasizing the key challenges that must be addressed before these insights can be reliably translated into obesity therapies.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, in which metabolic reprogramming plays a critical role in disease progression and organ failure. Metabolic reprogramming involves alterations in glucose, lipid, and protein metabolism, leading to imbalanced energy production, immune dysregulation, and tissue damage. Immune cells, under septic stress, switch to aerobic glycolysis, enhancing energy production but causing lactate accumulation and mitochondrial dysfunction, which exacerbates inflammation and organ injury. This metabolic shift emphasizes the need for personalized therapeutic strategies that address the metabolic heterogeneity between pathogens and hosts. The peroxisome proliferator-activated receptor (PPAR) pathway serves as a central regulator of both metabolic and immune responses, offering protective effects through the promotion of fatty acid oxidation and suppression of inflammation. However, the translational application of PPAR-directed therapies is constrained by limited drug specificity and significant interpatient heterogeneity. Advances in multiomics technologies provide promising opportunities for identifying metabolic biomarkers and tailoring PPAR-targeted treatments. Future research should focus on integrating metabolic pathways, developing precise diagnostic tools, and refining personalized interventions to improve sepsis management and patient prognosis. Unlike previous reviews that primarily focus on general immunometabolic alterations in sepsis, this review is the first to systematically integrate PPAR isoform-specific regulatory mechanisms, multiomics-based patient stratification, and phenotype-driven therapeutic targeting, thereby offering a novel framework for precision medicine in sepsis management. We critically evaluate the controversies on the efficacy of PPAR agonists, highlight cross talk with HIF-1α/NF-κB/Nrf2, and propose a phenotype-based stratification for sepsis therapy, a perspective that has not been explored in the literature.

[This corrects the article DOI: 10.1155/2021/6632137.].

The receptor known as peroxisome proliferator-activated receptor gamma (PPARγ) is crucial for effective wound healing, and recent progress has given a deeper understanding of its complex functions. As a biological switch, PPARγ regulates the immune response by shifting macrophages from promoting inflammation to supporting tissue regeneration, while suppressing pro-inflammatory signals to create an ideal healing environment. At the cellular level, PPARγ enhances the migration of keratinocytes and promotes re-epithelialization, thereby accelerating the wound closure process. It also promotes the differentiation of preadipocytes and the formation of new blood vessels, making a significant contribution to tissue regeneration. At the molecular level, PPARγ plays a dual role in guiding epithelial-mesenchymal transformation to aid healing while preventing excessive scarring. It improves mitochondrial efficiency to provide the energy needed for tissue repair. Despite these promising mechanisms, the clinical use of current PPARγ agonists faces hurdles due to side effects and regulatory hurdles. Moving forward, research should aim to develop targeted delivery methods, tailor therapies to individual needs, and investigate how PPARγ interacts synergistically with other signaling pathways, all of which are essential steps toward translating these findings into clinical practice.

Peroxisome proliferator-activated receptors (PPARs) modulate bile metabolism and are important therapeutic options in cholestatic diseases. This study was aimed at understanding the effects of single and multiple doses of seladelpar, a PPARδ (peroxisome proliferator-activated receptor delta) agonist, on plasma C4 (a freely diffusible metabolite accepted as a proxy for de novo bile acid biosynthesis), Fibroblast Growth Factor 21 (Fgf21), and gene expression changes in the liver of male and female mice. C57BL/6 mice were treated with seladelpar 10 mg/kg/day or vehicle through oral gavage before lights out on Day 1 (single dose) or from Day 1 to Day 7 (multiple doses). Liver samples were obtained at 0, 1, 2, 4, 8, 12, 16, and 24 h postdosing, and plasma C4 and Fgf21 levels were measured. In vehicle-treated mice, C4 levels were higher in the dark cycle compared to the light cycle, with higher levels in females than in males. Plasma Fgf21 did not vary substantially over the dark-light cycle or show a sex-specific expression pattern. Seladelpar treatment significantly reduced plasma C4 and increased Fgf21 levels in both sexes, which coincided with a decrease in cholesterol 7α-hydroxylase mRNA and an increase in Fgf21 mRNA in the livers. Untargeted RNA sequencing revealed a strong correlation between the genes differentially expressed after single- and multiple-dose seladelpar treatment. PPAR-responsive genes, including pyruvate dehydrogenase kinase 4, acyl-CoA thioesterase 2, and angiopoietin-like 4, were upregulated. No changes in nuclear receptors, clock genes, and sex-specific genes were observed. Overall, these results are consistent with a model where seladelpar treatment reduces bile acid synthesis by upregulating Fgf21 and modulating other PPAR-responsive genes.

Perivascular adipose tissue (PVAT) plays a crucial role in vascular homeostasis. Recent studies in adipose tissue demonstrated that endoplasmic reticulum (ER) stress and autophagy are activated in Type 2 diabetes mellitus (T2DM), while the precise role of ER stress and autophagy in PVAT is unclear. We aimed to investigate the possible influence of pioglitazone on ER stress and autophagy response in PVAT of T2DM rats. T2DM was induced by high-fat diet/low-dose streptozotocin (HFD/STZ) in male Wistar rats (8-10 weeks), and pioglitazone (20 mg/kg/p.o.) was administered for 6 weeks. Changes in biochemical parameters (nonfasting glucose, total cholesterol, and triglyceride) were verified in blood samples. ER stress-related (ATF4, CHOP, and GRP78) and autophagy-related (MAP1LC3B/LC3-II, BECN-1/Beclin, and SQSTM1/p62) gene expression levels in thoracic PVAT were measured by RT-PCR. Pioglitazone treatment reversed the increased nonfasting glucose and triglyceride levels in T2DM. ER stress and autophagy responses were significantly increased in PVAT of T2DM rats. Pioglitazone increased ER stress-related GRP78 gene expression while decreasing autophagy-related MAP1LC3B and BECN-1 gene expression levels in T2DM. Interestingly, SQSTM1 gene expression levels were increased by pioglitazone in the control and T2DM groups. The current study provides original findings regarding the effects of pioglitazone on ER stress and autophagy response in PVAT of HFD/STZ-induced T2DM rats. Pioglitazone treatment in T2DM increased GRP78 and SQSTM1 gene expressions, which both play a crucial role in adipocyte differentiation and adipogenesis, besides ER stress and autophagy. Further studies clarifying the adipogenic effect of pioglitazone on PVAT are needed for a better understanding of its effect on the vascular system.

Triple-negative breast cancer (TNBC) is highly heterogeneous and poses a significant medical challenge due to limited treatment options and poor outcomes. Peroxisome proliferator-activated receptors (PPARs) play a crucial role in regulating metabolism and cell fate. While the association between PPAR signal and human cancers has been a topic of concern, its specific relationship with TNBC remains unclear. Integrated analysis of large published datasets from clinical cohorts and cell lines through databases has proven to be a powerful and essential approach for understanding cancer and uncovering new molecular targets. Here, we conducted a comprehensive study investigating the clinical relevance and drug modulation of the PPAR signaling pathway in TNBC, using data from The Cancer Genome Atlas (TCGA) for TNBC patients and Genomics of Drug Sensitivity in Cancer (GDSC) for TNBC cell lines, along with drug perturbation information from Connectivity Map (CMap). In the TCGA-TNBC cohort, higher PPAR signaling activity was not associated with clinical stage, prognosis, tumor mutational burden, microsatellite instability, homologous recombination deficiency, stemness, or proliferation status. However, it was linked to older age; an elevated rate of piccolo presynaptic cytomatrix protein (PCLO) mutations; and oncogenic signal transduction involving MAPK, Ras, and PI3K-Akt pathways. Additionally, it influenced biological pathways including fatty acid metabolism, AMPK signaling, and ferroptosis. Strikingly, higher PPAR activity appeared to promote the formation of an antitumor immune and microbial microenvironment. In the GDSC-TNBC cells, nevertheless, it seemed to incur chemoresistance. Furthermore, we identified a batch of potential compounds that can regulate the PPAR signaling pathway. Lastly, our experimental validation demonstrated the ability of the histone deacetylase (HDAC) inhibitor chidamide to activate the PPAR signal in TNBC cells. In conclusion, the PPAR signaling pathway likely has pleiotropic biological effects in TNBC. These preliminary but interesting findings enhance our understanding of the role played by PPAR signal and provide new insights into the heterogeneity driven by it in TNBC.

Background: Hyperlipidemia is a critical risk factor for obesity, diabetes, cardiovascular diseases, and other chronic diseases. Our study was to determine the effects and mechanism of mangiferin (MF) and epigallocatechin gallate (EGCG) compounds on improving hyperlipidemia in HepG2 cells. Methods: HepG2 cells were treated with 0.25 mM palmitic acid (PA) and then incubated with MF (12.5, 25, and 50 μM) or EGCG (25, 50, and 100 μM) or MF:EGCG (0:0, 6.25:12.5, 25:50, and 50:100 μM:μM) for 24 h. The improvement of hyperlipidemia was verified by Oil Red O staining, changes in triglyceride (TG) and free fatty acid (FFA) levels, and the expression of lipid metabolizing proteins in western blotting. Results: MF (12.5, 25, and 50 μM) or EGCG (25, 50, and 100 μM) markedly lowered lipid accumulations by lipid index levels. Furthermore, we found that the optimum concentration of MF and EGCG compounds was 25:50 (μM:μM), which significantly reduced the FFA level, TG, and total cholesterol (TC) accumulations and increased FFA uptake in HepG2 cells, and the effect was better than that of single phytochemicals. The adenosine 5⁣'-monophosphate (AMP)-activated protein kinase (AMPK) protein and its downstream proteins sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor α (PPARα), and those involved in fatty acid translocase (CD36) and carnitine palmitoyltransferase 1 (CPT1) were also markedly increased in HepG2 cells. The upregulation of protein expression was reversed when AMPK-specific inhibitor Compound C was added. Conclusions: MF and EGCG (25:50 μM) compounds protect against hyperlipidemia by promoting the FFA oxidation, alleviating TG and TC accumulations via the AMPK/PPARα pathway in PA-treated HepG2 cells.

Paraquat (PQ) is an herbicide toxin that induces injury in different organs. The anti-inflammatory and antioxidant effects of carvacrol were reported previously. The effects of carvacrol and pioglitazone (Pio) alone and their combination on inhaled PQ-induced systemic and lung oxidative stress and inflammation as well as behavioral changes were examined in rats. In this study, animals were exposed to saline (control [Ctrl]) or PQ (PQ groups) aerosols. PQ-exposed animals were treated with 0.03 mg/kg/day dexamethasone (Dexa), 20 and 80 mg/kg/day carvacrol (C-L and C-H), 5 mg/kg/day Pio, and Pio+C-L for 16 days. Inhaled PQ markedly enhanced total and differential white blood cell (WBC) counts, nitric oxide (NO), and malondialdehyde (MDA) levels but decreased catalase (CAT) and superoxide dismutase (SOD) activities and thiol levels both in the bronchoalveolar lavage fluid (BALF) and blood and increased interferon-gamma (INF-γ) and interleukin-10 (IL-10) levels in the BALF (p < 0.001 for all cases) except lymphocyte count in blood which was not significantly changed. The escape latency and traveled distance were increased in the PQ group. However, the time spent in the target quadrant in the Morris water maze (MWM) test and the duration of time latency in the dark room in the shuttle box test were reduced after receiving an electrical shock (p < 0.05-p < 0.001). Inhaled PQ-induced changes were significantly improved in carvacrol, Pio, Dexa, and especially in the combination of the Pio+C-L treated groups (p < 0.05-p < 0.001). Carvacrol and Pio improved PQ-induced changes similar to Dexa, but ameliorative effects produced by combination treatments of Pio+C-L were more prominent than Pio and C-L alone, suggesting a potentiating effect for the combination of the two agents.