Atherosclerosis is the major pathological basis of cardiovascular diseases. Vascular smooth muscle cell (VSMC) dysfunction and death induced by oxidized low-density lipoprotein (oxLDL) play a key role in atherosclerosis. Ferroptosis is a novel iron-dependent lipid peroxidation regulated cell death, which is implicated in atherosclerosis. However, whether oxLDL induces VSMC ferroptosis and the specific mechanism is unclear.

To determine the effects of oxLDL on VSMC ferroptosis, LDH activity, MDA and Fe2+ content, glutathione peroxidase 4 (GPX4) expression and GPX enzyme activity were assayed. The level of lipid peroxidation was detected by C11 BODIPY fluorescence staining. RT-qPCR and Western blot were used to detect the mRNA and protein expressions of heat shock protein B1 (HSPB1), dipeptidyl peptidase 4 (DPP4) and nuclear factor kappa-B (NF-κB). The siRNAs, plasmids and Val-boropro were utilized to explore the roles of HSPB1/NF-κB/DPP4 in oxLDL-induced VSMC ferroptosis.

oxLDL increased LDH activity, Fe2+ content, lipid peroxidation and MDA content in VSMCs, which were inhibited by ferroptosis inhibitors Lip-1 and DFO. Moreover, oxLDL reduced GPX4 protein expression and GPX enzyme activity, indicating that oxLDL induces VSMC ferroptosis. Notably, HSPB1 inhibited oxLDL-induced VSMC ferroptosis by reducing the accumulation of Fe2+ and lipid peroxidation and increasing GPX4 expression and activity. In addition, HSPB1 suppressed oxLDL-induced VSMC ferroptosis by inhibiting DPP4 through NF-κB. Furthermore, Val-boropro could rescue oxLDL-induced ferroptosis in VSMCs with HSPB1 knockdown by inhibiting DPP4.

This study reveals for the first time that HSPB1 suppresses oxLDL-induced VSMC ferroptosis by inhibiting DPP4 through NF-κB, providing new strategies for the prevention and treatment of atherosclerosis.

Diabetes is a disease with a high global burden. Current strategies have failed to limit the advancement and impact of the disease. Successful early diagnosis and treatment will require the development of new agents. In this sense, boron-containing compounds have been reported as agents with the ability to reduce glycemia and lipidemia. They have also been used for labeling and measuring carbohydrates and other molecules linked to the initial stages of diabetes and its progression. In addition, certain boron compounds bind to molecules related to diabetes development and their biological activity in the regulation of elevated glycemia. Finally, it should be noted that some boron compounds appear to exert beneficial effects on diabetes complications such as accelerating wound healing while ameliorating pain in diabetic patients.

Fibroblast activation protein α (FAP) is expressed in normal adipose tissue and related to some pleiotropic metabolic regulators. However, the exact role and mechanism of FAP in obesity and related metabolic disorders are not well understood.

FAP knockout mice were fed a normal diet or a high-fat diet (HFD) for 12 weeks. FAP knockout mice or wild-type mice treated with an FAP inhibitor were subjected to cold stress for 5 days.

FAP deficiency protected mice against HFD-induced obesity and obesity-associated metabolic dysfunction, including glucose intolerance, insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia. Notably, FAP deficiency largely reversed obesity-induced adipose tissue macrophage accumulation and M1-M2 imbalance in white adipose tissue (WAT). Moreover, energy expenditure was significantly higher in FAP-deficient mice fed an HFD. Both FAP deficiency and inhibition increased cold tolerance through enhancing WAT beiging.

This study demonstrated that FAP deficiency protects mice against diet-induced obesity and related metabolic dysfunction. Furthermore, the protective effects are probably mediated via the promotion of WAT beiging and suppression of inflammation.

Inflammation and metabolic disorders are important factors in the occurrence and development of obesity complications. In this study, we investigated the protective effect and underlying mechanism of a novel pyrimidine-2,4-diamine derivative, Cyy-287, on mice fed a high-fat diet (HFD).

The mice were randomly separated into four groups (n ≥ 7): control (regular diet), HFD, HFD with Cyy-287 (5 mg/kg), and HFD with Cyy-287 (20 mg/kg) following HFD feeding for 10 weeks. After a 10-week administration, ALT and AST enzymes, echocardiography, immunohistochemical (IHC), Western blot (WB), Masson and Sirius Red staining were used to evaluate functional and morphological changes to the heart and liver. Microsomes from the mouse liver were extracted to quantify the total amount of CYP450 enzymes after drug treatment.

Cyy-287 decreased the levels of serum glucose, LDL, TC, ALT, and AST activities in HFD-treated mice. However, Cyy-287 administration increased ejection fraction (EF) and fractional shortening (FS) index of the heart. Cyy-287 inhibited histopathological changes in the heart and liver; decreased inflammatory activity; significantly diminished p38 mitogen-activated protein kinase (MAPK), the nuclear factor-kappa B (NF-κB) axis, and sterol regulatory element-binding protein-1c (SREBP-1c); and upregulated the AMP-activated protein kinase (AMPK) pathway in HFD-treated mice. Cyy-287 restored the content of hepatic CYP450 enzymes.

These findings demonstrated that Cyy-287 protected heart and liver cells from obesity-induced damage by inhibiting inflammation, fibrosis, and lipid synthesis.

Adipose tissue macrophages (ATM) are key players in the development of obesity and associated metabolic inflammation which contributes to systemic metabolic dysfunction. We here found that fibroblast activation protein α (FAP), a well-known marker of cancer-associated fibroblast, is selectively expressed in murine and human ATM among adipose tissue-infiltrating leukocytes. Macrophage FAP deficiency protects mice against diet-induced obesity and proinflammatory macrophage infiltration in obese adipose tissues, thereby alleviating hepatic steatosis and insulin resistance. Mechanistically, FAP specifically mediates monocyte chemokine protein CCL8 expression by ATM, which is further upregulated upon high-fat-diet (HFD) feeding, contributing to the recruitment of monocyte-derived proinflammatory macrophages with no effect on their classical inflammatory activation. CCL8 overexpression restores HFD-induced metabolic phenotypes in the absence of FAP. Moreover, macrophage FAP deficiency enhances energy expenditure and oxygen consumption preceding differential body weight after HFD feeding. Such enhanced energy expenditure is associated with increased levels of norepinephrine (NE) and lipolysis in white adipose tissues, likely due to decreased expression of monoamine oxidase, a NE degradation enzyme, by Fap-/- ATM. Collectively, our study identifies FAP as a previously unrecognized regulator of ATM function contributing to diet-induced obesity and metabolic inflammation and suggests FAP as a potential immunotherapeutic target against metabolic disorders.

The application of natural and synthetic boron-containing compounds (BCC) in biomedical field is expanding. BCC have effects in the metabolism of living organisms. Some boron-enriched supplements are marketed as they exert effects in the bone and skeletal muscle; but also, BCC are being reported as acting on the enzymes and transporters of membrane suggesting they could modify the carbohydrate metabolism linked to some pathologies of high global burden, as an example is diabetes mellitus. Also, some recent findings are showing effects of BCC on lipid metabolism. In this review, information regarding the effects and interaction of these compounds was compiled, as well as the potential application for treating human metabolic disorders is suggested.

The purpose of this study was to investigate the effects of aerobic exercise on the CHRONO-BMAL1 pathway and glucose metabolism in skeletal muscle of high-fat diet (HFD)-fed mice.

Male C57BL/6J mice were randomly allocated into four groups: normal chow diet with control (NCD + CON), NCD with exercise (NCD + EXE), HFD with control (HFD + CON) and HFD with exercise (HFD + EXE). The NCD and HFD groups were respectively fed a diet of 10 % and 60 % kilocalories from fat for 12 weeks. During the dietary intervention, EXE groups were subjected to 70 % VO_2max intensity of treadmill exercise six times per week for 12 weeks. Body weight, energy intake, fat weight, serum lipid profiles, systemic glucose homeostasis, the amount of CHRONO bound to BMAL1, the enzymatic activity, mRNA and protein expression involved in glucose metabolism of skeletal muscle were measured.

The results showed that the 12-week HFD feeding without exercise induced weight gain, serum dyslipidemia and insulin resistance. Furthermore, HFD increased the amount of CHRONO bound to BMAL1 and repressed the glucose metabolism in skeletal muscle. However, aerobic exercise prevented weight gain, serum dyslipidemia and systemic insulin resistance in the HFD-fed mice. Meanwhile, aerobic exercise also decreased the amount of CHRONO bound to BMAL1 and increased the glucose uptake, glucose oxidation and glycogenesis in skeletal muscle of the HFD-fed mice.

These data suggested that aerobic exercise could counterbalance CHRONO interacted with BMAL1 and prevent glucose metabolism dysfunction of skeletal muscle, and finally maintain whole-body insulin sensitivity in the HFD-fed mice.

Uterine fibroids (UF) represent an immense health burden throughout the world. Obesity is considered one of the risk factors for UF development; however, the underlying mechanisms remain largely unexplored. We investigated the effect of obesity on fibroblast activation and its association with inflammation, autophagy dysfunction, and oxidative stress in UF patients. Thirty-five pre-menopausal UF patients were included in this study and classified into non-obese group (BM1 ≤ 30 kg/m², n = 15) and obese group (BMI > 30 kg/m², n = 20). Tissue samples were collected from fibroids and adjacent normal myometrium. Our results showed increased expression of fibroblast activation protein (FAP) together with markers of autophagy, inflammation, and oxidative stress in UF patients, which were all more markedly upregulated in obese compared to non-obese patients. In addition, BMI was significantly positive correlated with FAP and autophagy markers. In conclusion, the results of the present study suggest that obesity-associated autophagy dysregulation together with increased FAP expression may increase the risk of UFs in obese women.