A Combination of a Dopamine Receptor 2 Agonist and a Kappa Opioid Receptor Antagonist Synergistically Reduces Weight in Diet-Induced Obese Rodents.

As the global obesity rate increases, so does the urgency to find effective anti-obesity drugs. In the search for therapeutic targets, central nervous system (CNS) mechanisms engaged in the regulation of energy expenditure and food intake, such as the opioid and dopamine systems, are crucial. In this study, we examined the effect on body weight of two drugs: bromocriptine (BC), a D2R receptor agonist, and PF-04455242, a selective κ opioid receptor (KOR) antagonist. Using diet-induced obese (DIO) rats, we aimed to ascertain whether the administration of BC and PF-04455242, independently or in combination, could enhance body weight loss. Furthermore, the present work demonstrates that the peripheral coadministration of BC and PF-04455242 enhances the reduction of weight in DIO rats and leads to a decrease in adiposity in a food-intake-independent manner. These effects were based on heightened energy expenditure, particularly through the activation of brown adipose tissue (BAT) thermogenesis. Overall, our findings indicate that the combination of BC and PF-04455242 effectively induces body weight loss through increased energy expenditure by increasing thermogenic activity and highlight the importance of the combined use of drugs to combat obesity.

p38α kinase governs muscle strength through PGC1α in mice.

AIMS: Skeletal muscle, with its remarkable plasticity and dynamic adaptation, serves as a cornerstone of locomotion and metabolic homeostasis in the human body. Muscle tissue, with its extraordinary capacity for force generation and energy expenditure, plays a fundamental role in the movement, metabolism, and overall health. In this context, we sought to determine the role of p38α in mitochondrial metabolism since mitochondrial dynamics play a crucial role in the development of muscle-related diseases that result in muscle weakness. METHODS: We conducted our study using male mice (MCK-cre, p38αMCK-KO and PGC1α MCK-KO) and mouse primary myoblasts. We analyzed mitochondrial metabolic, physiological parameters as well as proteomics, western blot, RNA-seq analysis from muscle samples. RESULTS: Our findings highlight the critical involvement of muscle p38α in the regulation of mitochondrial function, a key determinant of muscle strength. The absence of p38α triggers changes in mitochondrial dynamics through the activation of PGC1α, a central regulator of mitochondrial biogenesis. These results have substantial implications for understanding the complex interplay between p38α kinase, PGC1α activation, and mitochondrial content, thereby enhancing our knowledge in the control of muscle biology. CONCLUSIONS: This knowledge holds relevance for conditions associated with muscle weakness, where disruptions in these molecular pathways are frequently implicated in diminishing physical strength. Our research underscores the potential importance of targeting the p38α and PGC1α pathways within muscle, offering promising avenues for the advancement of innovative treatments. Such interventions hold the potential to improve the quality of life for individuals affected by muscle-related diseases.

MCJ: A mitochondrial target for cardiac intervention in pulmonary hypertension.

Pulmonary hypertension (PH) can affect both pulmonary arterial tree and cardiac function, often leading to right heart failure and death. Despite the urgency, the lack of understanding has limited the development of effective cardiac therapeutic strategies. Our research reveals that MCJ modulates mitochondrial response to chronic hypoxia. MCJ levels elevate under hypoxic conditions, as in lungs of patients affected by COPD, mice exposed to hypoxia, and myocardium from pigs subjected to right ventricular (RV) overload. The absence of MCJ preserves RV function, safeguarding against both cardiac and lung remodeling induced by chronic hypoxia. Cardiac-specific silencing is enough to protect against cardiac dysfunction despite the adverse pulmonary remodeling. Mechanistically, the absence of MCJ triggers a protective preconditioning state mediated by the ROS/mTOR/HIF-1α axis. As a result, it preserves RV systolic function following hypoxia exposure. These discoveries provide a potential avenue to alleviate chronic hypoxia-induced PH, highlighting MCJ as a promising target against this condition.

Stress kinases in the development of liver steatosis and hepatocellular carcinoma.

Non-alcoholic fatty liver disease (NAFLD) is an important component of metabolic syndrome and one of the most prevalent liver diseases worldwide. This disorder is closely linked to hepatic insulin resistance, lipotoxicity, and inflammation. Although the mechanisms that cause steatosis and chronic liver injury in NAFLD remain unclear, a key component of this process is the activation of stress-activated kinases (SAPKs), including p38 and JNK in the liver and immune system. This review summarizes findings which indicate that the dysregulation of stress kinases plays a fundamental role in the development of steatosis and are important players in inducing liver fibrosis. To avoid the development of steatohepatitis and liver cancer, SAPK activity must be tightly regulated not only in the hepatocytes but also in other tissues, including cells of the immune system. Possible cellular mechanisms of SAPK actions are discussed.

Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism.

Liver metabolism follows diurnal fluctuations through the modulation of molecular clock genes. Disruption of this molecular clock can result in metabolic disease but its potential regulation by immune cells remains unexplored. Here, we demonstrated that in steady state, neutrophils infiltrated the mouse liver following a circadian pattern and regulated hepatocyte clock-genes by neutrophil elastase (NE) secretion. NE signals through c-Jun NH2-terminal kinase (JNK) inhibiting fibroblast growth factor 21 (FGF21) and activating Bmal1 expression in the hepatocyte. Interestingly, mice with neutropenia, defective neutrophil infiltration or lacking elastase were protected against steatosis correlating with lower JNK activation, reduced Bmal1 and increased FGF21 expression, together with decreased lipogenesis in the liver. Lastly, using a cohort of human samples we found a direct correlation between JNK activation, NE levels and Bmal1 expression in the liver. This study demonstrates that neutrophils contribute to the maintenance of daily hepatic homeostasis through the regulation of the NE/JNK/Bmal1 axis.

Every day, the body's biological processes work to an internal clock known as the circadian rhythm. This rhythm is controlled by 'clock genes' that are switched on or off by daily physical and environmental cues, such as changes in light levels. These daily rhythms are very finely tuned, and disturbances can lead to serious health problems, such as diabetes or high blood pressure. The ability of the body to cycle through the circadian rhythm each day is heavily influenced by the clock of one key organ: the liver. This organ plays a critical role in converting food and drink into energy. There is evidence that neutrophils ­ white blood cells that protect the body by being the first response to inflammation ­ can influence how the liver performs its role in obese people, by for example, releasing a protein called elastase. Additionally, the levels of neutrophils circulating in the blood change following a daily pattern. Crespo, González-Terán et al. wondered whether neutrophils enter the liver at specific times of the day to control liver's daily rhythm. Crespo, González-Terán et al. revealed that neutrophils visit the liver in a pattern that peaks when it gets light and dips when it gets dark by counting the number of neutrophils in the livers of mice at different times of the day. During these visits, neutrophils secreted elastase, which activated a protein called JNK in the cells of the mice's liver. This subsequently blocked the activity of another protein, FGF21, which led to the activation of the genes that allow cells to make fat molecules for storage. JNK activation also switched on the clock gene, Bmal1, ultimately causing fat to build up in the mice's liver. Crespo, González-Terán et al. also found that, in samples from human livers, the levels of elastase, the activity of JNK, and whether the Bmal1 gene was switched on were tightly linked. This suggests that neutrophils may be controlling the liver's rhythm in humans the same way they do in mice. Overall, this research shows that neutrophils can control and reset the liver's daily rhythm using a precisely co-ordinated series of molecular changes. These insights into the liver's molecular clock suggest that elastase, JNK and BmaI1 may represent new therapeutic targets for drugs or smart medicines to treat metabolic diseases such as diabetes or high blood pressure.