Obesity is a complex, chronic disease and global public health challenge. Characterized by excessive fat accumulation in the body, obesity sharply increases the risk of several diseases, such as type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease, and is linked to lower life expectancy. Although lifestyle intervention (diet and exercise) has remarkable effects on weight management, achieving long-term success at weight loss is extremely challenging, and the prevalence of obesity continues to rise worldwide. Over the past decades, the pathophysiology of obesity has been extensively investigated, and an increasing number of signal transduction pathways have been implicated in obesity, making it possible to fight obesity in a more effective and precise way. In this review, we summarize recent advances in the pathogenesis of obesity from both experimental and clinical studies, focusing on signaling pathways and their roles in the regulation of food intake, glucose homeostasis, adipogenesis, thermogenesis, and chronic inflammation. We also discuss the current anti-obesity drugs, as well as weight loss compounds in clinical trials, that target these signals. The evolving knowledge of signaling transduction may shed light on the future direction of obesity research, as we move into a new era of precision medicine.

Tissue-tissue communication by endocrine factors is a vital mechanism for physiologic homeostasis. A systems genetics analysis of transcriptomic and functional data from a cohort of diverse, inbred strains of mice predicted that coagulation factor XI (FXI), a liver-derived protein, protects against diastolic dysfunction, a key trait of heart failure with preserved ejection fraction. This was confirmed using gain- and loss-of-function studies, and FXI was found to activate the bone morphogenetic protein (BMP)–SMAD1/5 pathway in the heart. The proteolytic activity of FXI is required for the cleavage and activation of extracellular matrix–associated BMP7 in the heart, thus inhibiting genes involved in inflammation and fibrosis. Our results reveal a protective role of FXI in heart injury that is distinct from its role in coagulation.

Septic cardiomyopathy is a life-threatening complication of severe sepsis and septic shock. Oxidative stress and mitochondrial dysfunction have been identified as significant abnormalities in septic cardiomyopathy. However, specific treatments are rare. This study aims to investigate the impact of β-hydroxybutyrate (β-OHB) on septic cardiomyopathy and explore the underlying mechanism(s). We found that pretreatment of D-β-hydroxybutyrate-(R)-1,3 butanediol monoester (ketone ester, 3 mg/g body weight, once daily) by gavage for three days elevated the levels of ketone bodies, especially that of β-hydroxybutyrate (β-OHB) in the circulation and mouse hearts, which exerted a protective effect against lipopolysaccharide (LPS, 20 mg/kg)-induced septic cardiomyopathy in mice. In addition, an LPS-stimulated macrophage-conditioned medium (MCM) was used to mimic the pathological process of septic cardiomyopathy. Mechanistically, β-OHB alleviated myocardial oxidative stress and improved mitochondrial respiratory function through the antioxidant FoxO3a/MT2 pathway activated via histone deacetylase (HDAC) inhibition, which ultimately enhanced heart performance in septic cardiomyopathy. Our results, therefore, suggested an unappreciated critical role of β-OHB in septic heart protection as well as highlighted the potential of β-OHB as a simple remedy for the septic cardiomyopathy population.

The current diagnostic criteria for cancer cachexia are inconsistent, and the prognostic value of cachexia in gastric cancer (GC) is controversial. This study aimed to investigate the prognostic value of the cachexia index (CXI) in patients with GC. We calculated the CXI as skeletal muscle index (SMI) × serum albumin/neutrophil-lymphocyte ratio (NLR), and a total of 161 and 163 patients were included in the high and low CXI groups, respectively. Low CXI was significantly associated with a more advanced tumor–node–metastasis (TNM) stage, a higher level of serum C-reactive protein, serum interleukin-6, and NLR, but also a decreased level of serum prealbumin and albumin. In addition, patients in the low CXI group were more likely to have postoperative pulmonary infections (9.8% vs. 3.7%, p = 0.03). Cox proportional analyses indicated that patients with low CXI (HR 0.45, 95% CI 0.29 to 0.69; p < 0.001) or TNM stage III+IV (HR 4.38, 95% CI 2.54 to 7.55; p < 0.001) had a significantly poorer overall survival (OS). Kaplan–Meier survival curves suggested that patients with low CXI had a significantly decreased OS, which was not affected by subgroup analyses of different sex, age, cachexia, body mass index (BMI), and TNM stage. Furthermore, low CXI combined with cachexia, low BMI, or TNM stage III+IV caused the worst OS in each subgroup analysis, respectively. Our study demonstrated that CXI had a good prognostic value in GC. Greater attention should be paid to patients with low CXI, particularly those combined with cachexia, low BMI, or TNM stage III+IV.

According to the latest Global Burden of Disease Study, cardiovascular disease (CVD) is the leading cause of death, and ischemic heart disease and stroke are the cause of death in approximately half of CVD patients. In CVD, mitochondrial dysfunction following ischemia-reperfusion (I/R) injury results in heart failure. The proper functioning of oxidative phosphorylation (OXPHOS) and the mitochondrial life cycle in cardiac mitochondria are closely related to mitochondrial DNA (mtDNA). Following myocardial I/R injury, mitochondria activate multiple repair and clearance mechanisms to repair damaged mtDNA. When these repair mechanisms are insufficient to restore the structure and function of mtDNA, irreversible mtDNA damage occurs, leading to mtDNA mutations. Since mtDNA mutations aggravate OXPHOS dysfunction and affect mitophagy, mtDNA mutation accumulation leads to leakage of mtDNA and proteins outside the mitochondria, inducing an innate immune response, aggravating cardiovascular injury, and leading to the need for external interventions to stop or slow the disease course. On the other hand, mtDNA released into the circulation after cardiac injury can serve as a biomarker for CVD diagnosis and prognosis. This article reviews the pathogenic basis and related research findings of mtDNA oxidative damage and mtDNA leak-triggered innate immune response associated with I/R injury in CVD and summarizes therapeutic options that target mtDNA.