Demethylation of N6-Methyladenosine (m6A) by fat mass and obesity-associated protein (FTO) occurs in the development of obesity and fatty liver disease. In this study, we synthesized FTO-degradation targeted chimera (FTO-DT), which exhibited excellent lipid-lowering activity at low concentration. At a concentration of 0.33 nM, the FTO-DT continuously and efficiently degraded FTO protein and reduced fat deposition. The FTO-DT improved energy metabolism and oxidative stress by increasing intracellular m6A levels, and further reduced fat deposition in hepatocytes, adipocytes, and mice fed a high-fat diet. The findings support the potential of FTO degradation by FTO-DT as a therapy for obesity and metabolic-associated fatty liver disease (MAFLD). This study provides a theoretical basis for the application of PROTACs in the treatment of metabolic disease and describes a novel approach for the development of drugs targeting metabolic disorders.

OBJECTIVE:Studies have shown a correlation between obesity and mitochondrial calcium homeostasis, yet it is unclear whether and how Mcu regulates adipocyte lipid deposition. This study aims to provide new potential target for the treatment of obesity and related metabolic diseases, and to explore the function of Mcu in adipose tissue.METHODS:We firstly investigated the role of mitoxantrone, an Mcu inhibitor, in the regulation of glucose and lipid metabolism in mouse adipocytes (3T3-L1 cells). Secondly, C57BL/6J mice were used as a research model to investigate the effects of Mcu inhibitors on fat accumulation and glucose metabolism in mice on a high-fat diet (HFD), and by using CRISPR/Cas9 technology, adipose tissue-specific Mcu knockdown mice (Mcufl/+ AKO) and Mcu knockout of mice (Mcufl/fl AKO) were obtained, to further investigate the direct effects of Mcu on fat deposition, glucose tolerance and insulin sensitivity in mice on a high-fat diet.RESULTS:We found the Mcu inhibitor reduced adipocytes lipid accumulation and adipose tissues mass in mice fed an HFD. Both Mcufl/+ AKO mice and Mcufl/fl AKO mice were resistant to HFD-induced obesity, compared to control mice. Mice with Mcufl/fl AKO showed improved glucose tolerance and insulin sensitivity as well as reduced hepatic lipid accumulation. Mechanistically, inhibition of Mcu promoted mitochondrial biogenesis and adipocyte browning, increase energy expenditure and alleviates diet-induced obesity.CONCLUSIONS:Our study demonstrates a link between adipocyte lipid accumulation and mCa2+ levels, suggesting that adipose-specific Mcu deficiency alleviates HFD-induced obesity and ameliorates metabolic disorders such as insulin resistance and hepatic steatosis. These effects may be achieved by increasing mitochondrial biosynthesis, promoting white fat browning and enhancing energy metabolism.

Nonalcoholic fatty liver disease (NAFLD) and obesity are nutritional metabolic diseases that are prevalent in the poultry industry, and have a negative impact on its functioning. Veratric acid (VA) is a phenolic acid compound extracted from the Chinese herbal medicine Trollius chinensis Bunge, known for its anti-inflammatory and antioxidant properties. In this study, we used chicken hepatocytes (Leghorn male hepatoma cells) and treated with a mixture of oleic acid and palmitic acid as well as Yellow-feathered broilers fed a high-fat diet to examine the impact of VA on liver-lipid metabolism and deposition of abdominal fat. The results showed that VA (1μM) reduced the triglyceride and total cholesterol levels in the chicken hepatocytes (p < 0.05). In the broiler NAFLD model, VA significantly reduced liver TG levels (p < 0.05) without affecting growth performance. Dietary supplementation with 0.05% or 0.1% VA supplementation also significantly reduced the mRNA expression levels of key genes involved in the synthesis of fatty acids such as sterol regulatory element-binding protein 1c, fatty acid synthase, and acetyl-CoA carboxylase in broiler livers. In addition, 0.1% VA reduced abdominal fat accumulation and improved blood biochemical indexes in broilers. Network pharmacology analysis suggested that VA may participate in regulating fat metabolism in broilers via the proliferator-activated receptor signaling pathway. Taken together, the study results support VA as a candidate feed additive to provide a novel strategy for preventing NAFLD and excessive fat deposition in chickens.

Metabolic-associated fatty liver disease (MAFLD) is a common chronic condition that poses a significant threat to human health. Mitochondrial dysfunction, particularly involving the mitochondrial Ca2+ uniporter (MCU), plays a key role in its pathogenesis. This study aimed to investigate the impact of the MCU gene on hepatic lipid metabolism in mice fed a high-fat diet. Using MCU knockout and wild-type mice, subjected to either a high-fat or normal diet for 14 weeks, we observed notable Steatosis and liver weight gain in MCU-deficient mice. Liver function markers, serum triglycerides, very low-density lipoprotein (VLDL) levels, and ApoB protein expression were all significantly elevated. Mechanistic studies revealed that MCU deletion led to mitochondrial dysfunction, increased oxidative stress. These findings highlight the critical role of the MCU gene in maintaining hepatic lipid balance and suggest its potential as a therapeutic target for managing nonalcoholic fatty liver disease.

Obesity is of public concern worldwide, and it increases the probability of developing a number of comorbid diseases, including NAFLD. Recent research on obesity drugs and health demands have shown the potential of natural plant extracts for preventing and treating obesity and their lack of toxicity and treatment-related side effects. We have demonstrated that tuberostemonine (TS), an alkaloid extracted from the traditional Chinese medicine Stemona tuberosa Lour can inhibit intracellular fat deposition, reduce oxidative stress, increase cellular adenosine triphosphate (ATP), and increase mitochondrial membrane potential. It effectively reduced weight gain and fat accumulation caused by a high-fat diet, and regulated liver function and blood lipid levels. Moreover, it regulate glucose metabolism and improved energy metabolism in mice. TS also decreased high-fat diet-induced obesity and improved lipid and glucose metabolism disorders in mice, with no significant side effects. In conclusion, TS was shown to be a safe alternative for obese patients and might be developed as an antiobesity and anti-nonalcoholic fatty liver drug.

The rising prevalence of nonalcoholic fatty liver disease (NAFLD) has become a global health threat that needs to be addressed urgently. Basic leucine zipper ATF-like transcription factor (BATF) is commonly thought to be involved in immunity, but its effect on lipid metabolism is not clear. Here, we investigated the function of BATF in hepatic lipid metabolism. BATF alleviated high-fat diet (HFD)-induced hepatic steatosis and inhibited elevated programmed cell death protein (PD)1 expression induced by HFD. A mechanistic study confirmed that BATF regulated fat accumulation by inhibiting PD1 expression and promoting energy metabolism. PD1 antibodies alleviated hepatic lipid deposition. In conclusion, we identified the regulatory role of BATF in hepatic lipid metabolism and that PD1 is a target for alleviation of NAFLD. This study provides new insights into the relationship between BATF, PD1 and NAFLD.

As living standards improve, obesity has become an increasingly serious health problem. Natural extracts from a wide range of sources are non-toxic and have significant potential as drugs for the prevention and treatment of obesity. We assessed 243 natural small molecules in a HepG2 fat accumulation model and found that epigoitrin (EP) from Radix isatidis reduced intracellular fat deposition, increased short-chain acyl CoA dehydrogenase (SCAD) activity, promoted glucose uptake and glycogen storage, increased ATP production and reduced glutathione (GSH) content, reduced reactive oxygen species (ROS), and enhanced superoxide dismutase (SOD) activity. In a murine high-fat diet model, the addition of EP to the high-fat diet significantly reduced fat deposition, increased glucose tolerance, improved insulin sensitivity, and increased energy expenditure. In conclusion, EP alleviated obesity caused by a high-fat diet and improved disorders of lipid and glucose metabolism.

The small intestine is main site of exogenous lipid digestion and absorption, and it is important for lipid metabolic homeostasis. Cell death-inducing DNA fragmentation-factor like effector C (CIDEC) is active in lipid metabolism in tissues other than those in the intestine. We developed small intestine-specific CIDEC (SI-CIDEC-/-) knockout C57BL/6J mice by Cre/LoxP recombination to investigate the in vivo effects of intestinal CIDEC on lipid metabolism. Eight-week-old SI-CIDEC-/- mice fed a high-fat diet for 14 weeks had 15% lower body weight, 30% less body fat mass, and 79% lower liver triglycerides (TG) than wild-type (WT) mice. In addition, hepatic steatosis and fatty liver inflammation were less severe in knockout mice fed a high-fat diet (HFD) compared with wild-type mice fed an HFD. SI-CIDEC-/- mice fed an HFD diet had lower serum TG and higher fecal TG and intestinal lipase activity than wild-type mice. Mechanistic studies showed that CIDEC accelerated phosphatidic acid synthesis by interacting with 1-acylglycerol-3-phosphate-O-acyltransferase to promote TG accumulation. This study identified a new interacting protein and previously unreported CIDEC mechanisms that revealed its activity in lipid metabolism of the small intestine.

Meat is an essential food, and pork is the largest consumer meat product in China and the world. Intramuscular fat has always been the basis for people to select and judge meat products. Therefore, we selected the Duroc, a western lean pig breed, and the Luchuan, a Chinese obese pig breed, as models, and used the longissimus dorsi muscle for lipidomics testing and transcriptomics sequencing. The purpose of the study was to determine the differences in intramuscular fat between the two breeds and identify the reasons for the differences. We found that the intramuscular fat content of Luchuan pigs was significantly higher than that of Duroc pigs. The triglycerides and diglycerides related to flavor were higher in Luchuan pigs compared to Duroc pigs. This phenotype may be caused by the difference in the expression of key genes in the glycerolipid metabolism signaling pathway.

Background In the livestock industry, intramuscular fat content is a key factor affecting meat quality. Many studies have shown that dietary calcium supplementation is closely related to lipid metabolism. However, few studies have examined the relationship between dietary calcium supplementation and intramuscular fat accumulation. Methods Here, we used C2C12 cells, C57BL/6 mice ( n = 8) and three-way cross-breeding pigs (Duroc×Landrace×Large white) ( n = 10) to study the effect of calcium addition on intramuscular fat accumulation. In vitro, we used calcium chloride to adjust the calcium levels in the medium (2 mmol/L or 3 mmol/L). Then we measured various indicators. In vivo , calcium carbonate was used to regulate calcium levels in feeds (Mice: 0.5% calcium or 1.2% calcium) (Pigs: 0.9% calcium or 1.5% calcium). Then we tested the mice gastrocnemius muscle triglyceride content, pig longissimus dorsi muscle meat quality and lipidomics. Results In vitro , calcium addition (3 mmol/L) had no significant effect on cell proliferation, but promoted the differentiation of C2C12 cells into slow-twitch fibers. Calcium supplementation increased triglyceride accumulation in C2C12 cells. Calcium addition increased the number of mitochondria and also increased the calcium level in the mitochondria and reduced the of key enzymes activity involved in β-oxidation such as acyl-coenzyme A dehydrogenase. Decreasing mitochondrial calcium level can alleviate lipid accumulation induced by calcium addition. In addition, calcium addition also reduced the glycolytic capacity and glycolytic conversion rate of C2C12 cells. In vivo , dietary calcium supplementation (1.2%) promoted the accumulation of triglycerides in the gastrocnemius muscle of mice. Dietary calcium supplementation (1.5%) had no effect on pig weight, but significantly improved the flesh color of the longissimus dorsi muscle, reduced the backfat thickness and increased intramuscular fat content in pigs. Besides, calcium addition had no effect on longissimus dorsi pH, electrical conductivity and shear force. Conclusions These results suggest that calcium addition promotes intramuscular fat accumulation by inhibiting the oxidation of fatty acids. These findings provide a new tool for increasing intramuscular fat content and an economical strategy for improving meat quality.