Donkey milk has garnered increasing attention due to its remarkable similarity to human milk and its diverse bioactive properties. Analysis of its composition shows that donkey milk is characterized by high lactose content, low protein, low fat, a balanced calcium-to‑phosphorus ratio, and abundant in vitamins C and D, making it a promising human milk alternative. Additionally, donkey milk contains a unique composition of whey proteins and polyunsaturated fatty acids, contributing to its beneficial health effects such as antimicrobial, anti-inflammatory, antioxidant, and hypoallergenic properties. This review provides a comprehensive analysis of the nutritional profile of donkey milk in comparison to other mammalian milk sources. Furthermore, it highlights its bioactive potential and discusses the current challenges and future opportunities for expanding its applications in the dairy and health industries. Despite its valuable properties, the development of donkey milk products remains limited due to low milk yield and high production costs. Further research and technological advancements are necessary to optimize its utilization and commercial potential.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide for which there is only one approved treatment. Adenosine monophosphate-activated protein kinase (AMPK) is an interesting therapeutic target since it acts as a central regulator of cellular metabolism. Despite efforts to target AMPK, no direct activators have yet been approved for treatment of this disease. This study investigated the effect of the AMPK activator ATX-304 in a preclinical mouse model of progressive fatty liver disease. The data demonstrated that ATX-304 diminishes body fat mass, lowers blood cholesterol levels, and mitigates general liver steatosis and the development of liver fibrosis, but with pronounced local heterogeneities. The beneficial effects of ATX-304 treatment were accompanied by a shift in the liver metabolic program, including increased fatty acid oxidation, reduced lipid synthesis, as well as remodeling of cholesterol and lipid transport. We also observed variations in lipid distribution among liver lobes in response to ATX-304, and a shift in the zonal distribution of lipid droplets upon treatment. Taken together, our data suggested that ATX-304 holds promise as a potential treatment for MASLD.

Thyroid hormones (THs) are key modulators of energy metabolism and cross-talk with other endocrine and metabolic factors. Notably, leptin can increase hypothalamic control of TH synthesis as an adaptive metabolic response regulating body weight. In this study, we found that the TH signal is heightened in overweight humans and is lost with obesity. In mice, systemic and intracerebroventricular leptin injection induces the expression of type 2 deiodinase (D2), the TH-activating enzyme, in skeletal muscle. Mechanistically, leptin enhances the transcription of D2 by a STAT3- and α-melanocyte-stimulating hormone (α-MSH)/cyclic AMP (cAMP)-dependent regulation. Notably, mice lacking D2 or with a mutation in the TH receptor do not exhibit the metabolic effects of leptin, such as increased insulin sensitivity and oxygen consumption, indicating that leptin's peripheral metabolic effects in skeletal muscle are mediated by TH. These findings underscore the critical role of leptin in integrating the TH-induced metabolic activation, while also contributing to appetite suppression in response to perceived fat stores.

This study aimed to investigate the effects of a diet supplemented with different levels of oleic acid (OA) on growth performance, serum biochemical parameters, nutrient utilization, and intestinal lipid metabolism in Pekin ducks. A total of 350 fourteen-d-old male ducks were randomly assigned to the following five isonitrogenous and heteroenergetic dietary treatment groups: 0.00% (control), 0.25%, 0.50%, 0.75%, and 1.00% OA groups. The experiment lasted 28 days. The findings indicated that neither growth performance nor nutrient utilization was affected by OA supplementation (P > 0.05). The 0.50% OA group displayed the lowest serum triglyceride (TG) levels among all treatment groups, with significantly lower values compared to both the 0.25%=% and 0.75% OA groups (P < 0.05). Moreover, the activities of lipid droplet (LD)-degrading enzymes in the jejunal mucosa, such as adipose triglyceride lipase (ATGL), showed a significant inverse linear relationship (P < 0.05); carboxylesterase 2 (CES2) activity exhibited a proportional dose-dependent increase (P < 0.05); and lysosomal acid lipase (LAL) activity was negatively correlated with the increased concentration of OA in the diet (P < 0.05). Moreover, the mRNA expression levels of the LD formation-related genes PLIN2 were significantly higher in the 0.50% OA group compared to the 0.25% and 0.75% OA groups (P < 0.05). The mRNA expression of LD degradation-related genes, the PNPLA2 expression in the 0.25%, 0.50%, and 0.75% OA groups and LPL expression in all OA groups were downregulated (P < 0.05) when compared with those in the control group. These results suggested that dietary supplementation with OA, especially at a level of 0.50%, may decrease the serum TG content and promote lipid deposition in the jejunum in Pekin ducks by regulating the formation and degradation of enterocyte LDs.

Amid a rising prevalence of non-alcoholic fatty liver disease (NAFLD), there is still an unmet need to better treat it. We identified a secreted factor, Meteorin-like (Metrnl), with decreased levels in livers with hepatic steatosis. Notably, recombinant Metrnl ameliorated hepatic steatosis in NAFLD mouse models. Mechanistically, Metrnl exerted dual effects by promoting triglyceride (TG) transportation by the phosphatidylinositol 3-kinase (PI3K)/Akt/Sp1/cytidylyltransferase α (CCTα) axis, thereby increasing the biosynthesis of phosphatidylcholine (PC) to facilitate TG secretion from the liver while facilitating AMP-activated protein kinase (AMPK)-dependent fatty acid oxidation (FAO). Exogenous injection of cytidine diphosphocholine (CDP)-choline, the production of CCTα, to increase PC synthesis, was shown to restore the inhibition of TG secretion in hepatic Metrnl-deficient (LKO-Met) mice. Combining CDP-choline and an AMPK activator was sufficient to rescue hepatic steatosis in LKO-Met mice. Collectively, these findings reveal unexpected roles of Metrnl as a factor in PC biosynthesis, TG secretion, and FAO, suggesting potential therapeutic application for NAFLD.

Lipid metabolism is a well-regulated process essential for maintaining cellular functions and energy homeostasis. Dysregulation of lipid metabolism is associated with various conditions, including cardiovascular diseases, neurodegenerative disorders, and metabolic syndromes. This review explores the mechanisms underlying lipid metabolism, emphasizing the roles of key lipid species such as triglycerides, phospholipids, sphingolipids, and sterols in cellular physiology and pathophysiology. It also examines the genetic and environmental factors contributing to lipid dysregulation and the challenges of diagnosing and managing lipid-related disorders. Recent advancements in lipid-lowering therapies, including PCSK9 inhibitors, ezetimibe, bempedoic acid, and olpasiran, provide promising treatment options. However, these advancements are accompanied by challenges related to cost, accessibility, and patient adherence. The review highlights the need for personalized medicine approaches to address the interplay between genetics and environmental factors in lipid metabolism. As lipidomics and advanced diagnostic tools continue to progress, a deeper understanding of lipid-related disorders could pave the way for more effective therapeutic strategies.

Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.

Obesity leads to the development of several diseases and chronic death worldwide. Mitochondrial dysfunction is one of the vital causes to develop obesity. Targeting mitochondrial uncoupling protein 1 (UCP1) may well be a potential therapeutic approach against obesity or mitochondrial dysfunction-related illnesses. To assess the significance of mitochondrial adenosine triphosphate (ATP) synthesis, mitochondrial DNA quantity and in vitro pharmacodynamics and pharmacokinetics, we used CX-6258 HCl (pan-Pim kinase inhibitor) in this work. CX-6258 HCl significantly reduces ATP production both in white and brown adipocytes and, therefore, improves thermogenesis, which helps to reduce fat in adipocytes. On the HEK293T cell line, no appreciable cell growth was seen. The in silico analysis identifies a potential interaction between CX-6258 HCl and the UCP1 protein. To treat disorders linked to mitochondrial dysfunction or obesity, CX-6258 HCl may be a promising therapeutic option. The role of pan-Pim kinase inhibitor on obesity and mitochondrial dysfunction-related disorders remains unknown. Further investigation will be leading to the development of the mechanism of action and therapeutic potential of CX-6258 HCl (pan-Pim kinase inhibitor).

The dorsomedial hypothalamus (DMH) receives inputs from the preoptic area (POA), where ambient temperature mediates physiological adaptations of energy expenditure and food intake. Warm-activated POA neurons suppress energy expenditure via brown adipose tissue (BAT) projecting neurons in the dorsomedial hypothalamus/dorsal hypothalamic area (dDMH/DHA). Our earlier work identified leptin receptor (Lepr)-expressing, BAT-projecting dDMH/DHA neurons that mediate metabolic leptin effects. Yet, the neurotransmitter (glutamate or GABA) used by dDMH/DHALepr neurons remains unexplored and was investigated in this study using mice. We report that dDMH/DHALepr neurons represent equally glutamatergic and GABAergic neurons. Surprisingly, chemogenetic activation of glutamatergic and/or GABAergic dDMH/DHA neurons were capable to increase energy expenditure and locomotion, but neither reproduced the beneficial metabolic effects observed after chemogenetic activation of dDMH/DHALepr neurons. We clarify that BAT-projecting dDMH/DHA neurons that innervate the raphe pallidus (RPa) are exclusively glutamatergic Lepr neurons. In contrast, projections of GABAergic or dDMH/DHALepr neurons overlapped in the ventromedial arcuate nucleus (vmARC), suggesting distinct energy expenditure pathways. Brain slice patch clamp recordings further demonstrate a considerable proportion of leptin-inhibited dDMH/DHALepr neurons, while removal of pre-synaptic (indirect) effects with synaptic blocker increased the proportion of leptin-activated dDMH/DHALepr neurons, suggesting that pre-synaptic Lepr neurons inhibit dDMH/DHALepr neurons. We conclude that stimulation of BAT-related, GABA- and glutamatergic dDMH/DHALepr neurons in combination mediate the beneficial metabolic effects. Our data support the idea that dDMH/DHALepr neurons integrate upstream Lepr neurons (e.g., originating from POA and ARC). We speculate that these neurons manage dynamic adaptations to a variety of environmental changes including ambient temperature and energy state. SIGNIFICANCE STATEMENT: Our earlier work identified leptin receptor expressing neurons in the dDMH/DHA as an important thermoregulatory site. Dorsomedial hypothalamus (DMH) Lepr neurons participate in processing and integration of environmental exteroceptive signals like ambient temperature and circadian rhythm, as well as interoceptive signals including leptin and the gut hormone glucagon-like-peptide-1 (GLP1). The present work further characterizes dDMH/DHALepr neurons as a mixed glutamatergic and GABAergic population, but with distinct axonal projection sites. Surprisingly, select activation of glutamatergic and/or GABAergic populations are all able to increase energy expenditure, but are unable to replicate the beneficial metabolic effects observed by Lepr activation. These findings highlighting dDMH/DHA Lepr neurons as a distinct subgroup of glutamatergic and GABAergic neurons that are under indirect and direct influence of the interoceptive hormone leptin and if stimulated are uniquely capable to mediate beneficial metabolic effects. Our work significantly expands our knowledge of thermoregulatory circuits and puts a spotlight onto DMH-Lepr neurons for the integration into whole body energy and body weight homeostasis.

Background/Objectives: The backfat thickness of pigs is closely related to dorsal subcutaneous fat deposition and meat quality, and appropriate reduction in backfat thickness is important for improving pork quality. The present study investigated the effect of acorn diet on the backfat thickness and lipase activity of Yuxi black pigs and to gain further insight into the molecular mechanism of the acorn diet on the dorsal subcutaneous fat deposition of Yuxi black pigs by transcriptome sequencing (RNA-seq). Methods: Thirty-six Yuxi black pigs with an initial body weight of 99.60 ± 2.32 kg (three replicates per group and six pigs per replicate) were randomly divided into two groups (CON group was fed a basic diet and AEG group was fed 30% acorn diets). Pigs were individually fed twice daily and had access to water ad libitum throughout the experiment. The test period was 4 months. Results: Results showed that backfat thickness and ACC, MDH, and LPL lipase activities were significantly reduced in the AEG group than in the CON group (p < 0.05). In addition, RNA-seq identified 826 differentially expressed genes (DEGs), with 505 up-regulated and 321 down-regulated. The DEGs were significantly enriched in the lipid metabolism process and lipid catabolic process, fatty acid (FA) catabolic process, and FA β-oxidation according to GO enrichment analysis. LEP, CHPT1, UCP3, ACOX1, SCD5, and ACAA1 were screened as key differential genes regulating dorsal subcutaneous fat deposition. Conclusions: The above results indicated that feeding the 30% acorn diet could regulate the expression of genes involved in fat deposition and reduce lipase activity, thereby decreasing the backfat thickness, inhibiting the deposition of dorsal subcutaneous fat, and improving the pork quality. The findings of this experiment established a basis for subsequent research into the molecular mechanisms underlying the impact of acorn diets on fat deposition in Yuxi black pigs and provided the scientific evidence to promote the exploitation and industrialization of acorns.

MicroRNAs play a pivotal role in the regulation of adipose tissue function and have emerged as promising therapeutic candidates for the management of obesity and associated comorbidities. Among them, miR-1 could be a potential biomarker for metabolic diseases and contribute to metabolic homeostasis. However, thorough research is required to fully elucidate the impact of miR-1 on human adipocyte thermogenesis and metabolism. This study aimed to explore the effect of miR-1 on human adipocyte browning, a process whose activation has been linked to obesity protection and counteraction. Human multipotent adipose-derived stem cells, hMADS cells, were differentiated into white and brown-like adipocytes and transfected with miR-1 mimics for gene expression and western blotting analyses. miR-1 inhibited the expression of its previously validated target PTK9/TWF1 and modulated the expression profile of key genes involved in thermogenesis and adipocyte browning (increased UCP1 at mRNA and protein level, increased CPT1M, decreased HIF3A), adipocyte differentiation and metabolism (decreased PLIN1, FASN, RXRA, PPARG, FABP4, MAPKAPK2), as well as genes related to the cytoskeleton (decreased ACTB) and extracellular matrix (decreased COL1A1). These findings suggest that miR-1 can modulate the expression of adipocyte human genes associated with thermogenesis and metabolism, which could hold value for eventual therapeutic potential in obesity.

The cloning of leptin 30 years ago in 1994 was an important milestone in obesity research. Prior to the discovery of leptin, obesity was stigmatized as a condition caused by lack of character and self-control. Mutations in either leptin or its receptor were the first single gene mutations found to cause severe obesity, and it is now recognized that obesity is caused mostly by a dysregulation of central neuronal circuits. Since the discovery of the leptin-deficient obese mouse (ob/ob) the cloning of leptin (ob aka lep) and leptin receptor (db aka lepr) genes, we have learned much about leptin and its action in the central nervous system. The first hope that leptin would cure obesity was quickly dampened because humans with obesity have increased leptin levels and develop leptin resistance. Nevertheless, leptin target sites in the brain represent an excellent blueprint to understand how neuronal circuits control energy homeostasis. Our expanding understanding of leptin function, interconnection of leptin signaling with other systems and impact on distinct physiological functions continues to guide and improve the development of safe and effective interventions to treat metabolic illnesses. This review highlights past concepts and current emerging concepts of the hormone leptin, leptin receptor signaling pathways and central targets to mediate distinct physiological functions.

The transient postnatal increase in circulating leptin levels, known as leptin surge, may increase later susceptibility to diet-induced obesity in rodents. However, the source of leptin during the surge needs to be better characterized, and the long-term effects of leptin are contradictory. Characterization of the interaction of leptin with the genetic background, sex, and other factors is required. Here, we focused on the impact of circulating leptin levels and several related variables, measured in 2- and 4-wk-old i) obesity-prone C57BL/6 (B6) and ii) obesity-resistant A/J mice. In total, 264 mice of both sexes were used. Posttranscriptionally controlled leptin secretion from subcutaneous white adipose tissue, the largest adipose tissue depot in mice pups, was the primary determinant of plasma leptin levels. When the animals were randomly assigned standard chow or high-fat diet (HFD) between 12 and 24 wk of age, the obesogenic effect of HFD feeding was observed in B6 but not A/J mice. Only leptin levels at 2 wk, i.e., close to the maximum in the postnatal leptin surge, correlated with both body weight (BW) trajectory throughout the life and adiposity of the 24-wk-old mice. Leptin surge explained 13 and 7% of the variance in BW and adiposity of B6 mice, and 9 and 35% of the variance in these parameters in A/J mice, with a minor role of sex. Our results prove the positive correlation between the leptin surge and adiposity in adulthood, reflecting the fundamental biological role of leptin. This role could be compromised in subjects with obesity.NEW & NOTEWORTHY The postnatal surge in circulating leptin levels in mice reflects particularly posttranscriptionally controlled release of this hormone from subcutaneous white adipose tissue. Leptinemia in 2-wk-old pups predicts both body weight and adiposity in adult mice fed a high-fat diet. The extent of these effects depends on genetically determined differences in propensity to obesity between C57BL/6 and A/J mice. The leptin effect on adiposity is compromised in the obesity-prone C57BL/6 mice.

Obesity is a major risk factor for many life-threatening diseases. Adipose tissue dysfunction is emerging as a driving factor in the transition from excess adiposity to comorbidities such as metabolic-associated fatty liver disease, cardiovascular disease, Type 2 diabetes and cancer. However, the transition from healthy adipose expansion to the development of these conditions is poorly understood. Adipose stem cells, residing in the vasculature and stromal regions of subcutaneous and visceral depots, are responsible for the expansion and maintenance of organ function, and are now recognised as key mediators of pathological transformation. Impaired tissue expansion drives inflammation, dysregulation of endocrine function and the deposition of lipids in the liver, muscle and around vital organs, where it is toxic. Contrary to previous hypotheses, it is the promotion of healthy adipose tissue expansion and function, not inhibition of adipogenesis, that presents the most attractive therapeutic strategy in the treatment of metabolic disease. AMP-activated protein kinase, a master regulator of energy homeostasis, has been regarded as one such target, due to its central role in adipose tissue lipid metabolism, and its apparent inhibition of adipogenesis. However, recent studies utilising AMP-activated protein kinase (AMPK)-specific compounds highlight a more subtle, time-dependent role for AMPK in the process of adipogenesis, and in a previously unexplored repression of leptin, independent of adipocyte maturity. In this article, I discuss historic evidence for AMPK-mediated adipogenesis inhibition and the multi-faceted roles for AMPK in adipose tissue.

Leptin plays an indispensable role in energy homeostasis, and its involvement in metabolic activities has been extensively explored in fish. We generated mutant lines of leptina (-5 bp) and leptinb (+8 bp) in zebrafish using CRISPR/Cas9 technology to explore the metabolic characteristics of lepa and lepb mutant zebrafish in response to high glucose nutritional stress induced by high levels of carbohydrates. The results were as follows: the body weight and food intake of adult zebrafish of the two mutant species were increased; the visceral fat accumulation, whole-body crude lipid, and crude protein contents of lepb-/- were increased; and the visceral fat accumulation and crude lipid in lepa-/- zebrafish were decreased. The blood glucose levels of the two mutant zebrafish were increased, the mRNA expression levels of glycolytic genes pk and gck were decreased in the two mutant zebrafish, and there were differences between lepa-/- and lepb-/- zebrafish. The expressions of glycogen synthesis and decomposition genes were inhibited and promoted, respectively. The expression of adipose synthesis genes in the liver and muscle was stimulated in lepb-/- zebrafish but suppressed in lepa-/- zebrafish. Lipolysis and oxidation genes were also stimulated in lepa-/- zebrafish livers, while the livers of lepb-/- zebrafish were stimulated but muscle was inhibited. In conclusion, the results indicate that lepa plays a major role in glucose metabolism, which is conducive to promoting glucose utilization and lipogenesis, while lepb mainly promotes lipolysis and oxidation, regulates protein generation, and plays a minor role in glucose metabolism.

Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver disorder, has garnered increasing attention globally owing to its associated health complications. However, the lack of available therapeutic medications and inadequate management of complications in metabolic dysfunction-associated steatohepatitis (MASH) present significant challenges. There are little studies evaluating the effectiveness of POM in treating MASLD. In this study, we synthesized polyoxometalates (POM) for potential treatment of MASLD.

We induced liver disease in mice using two approaches: feeding a high-fat diet (HFD) to establish MASLD or feeding a methionine-choline deficient (MCD) diet to induce hepatic lipotoxicity and MASH. Various metabolic parameters were detected, and biochemical and histological evaluations were conducted on MASLD. Western blotting, qRT-PCR and immunofluorescence assays were used to elucidate the molecular mechanism of POM in the treatment of MASLD.

POM therapy resulted in significant improvements in weight gain, dyslipidemia, liver injury, and hepatic steatosis in mice fed a HFD. Notably, in a more severe dietary-induced MASH model with MCD diet, POM significantly attenuated hepatic lipid accumulation, inflammation, and fibrosis. POM treatment effectively attenuated palmitic acid and oleic acid-induced lipid accumulation in HepG2 and Huh7 cells by targeting the AMPK pathway to regulate lipid metabolism, which was confirmed by AMPK inhibitor. Additionally, the activation of AMPK signaling by POM suppressed the expression of lipid synthesis genes, including sterol regulatory element-binding protein 1c (SREBP1c) and SREBP2, while concurrently upregulating the expression of sirtuin 1 (SIRT1) to promote fatty acid oxidation.

These findings suggest that POM is a promising therapeutic strategy with high efficacy in multiple MASLD models.

Objective: We investigated whether the results of leptin gene (LEP) 2548G/A (rs7799039) and leptin receptor gene (LEPR) 668 A/G (rs1137101) variants, as well as the methylation analysis of CpG regions at nucleotides -31 and -51 of the LEP gene, showed any differences between breastfed and non-breastfed children in this study. Materials and Methods: The cross-sectional study included 100 children aged 2-5 years who were attending nursery and kindergarten and had been accepted to the Department of General Paediatrics. Infants who were exclusively breastfed for the first six months after birth constituted the study group, and those who were not only breastfeed constituted the control group. Methylation percentages at CpG islands of the LEP gene were compared between exclusively breastfed and non-exclusively breastfed infants, and the statistical significance was analyzed by looking for changes in LEP -31 and -51 nt methylation and LEP 2548G/A ve LEPR 668 A/G variants. Results: Both groups were compared by feeding, and the association of LEPR and LEP gene polymorphisms and -51 nt and -31 nt methylations were analyzed. There were no significant differences between the groups regarding genotype and allele frequency for the LEPR 668 A/G, LEP 2548 G/A gene variant, -31 nt methylation, and -51 nt methylation status. Similarly, there was no significant difference in genotype and allele frequency for the LEPR 668 A/G gene variant in terms of duration of exclusive breastfeeding, total breastfeeding, body mass index, family obesity, and satiety status. However, maternal support from family elders and physical activity increased the 51 nt methylation, but this methylation was not significantly affected by BMI, age, or satiety status. Conclusions: Maternal support from family elders and physical activity were associated with increased 51 nt methylation, but this methylation was not significantly affected by BMI, age, or satiety status. However, there are not enough studies in this area to reach a definitive conclusion, and further research is needed.

In the present scenario, obesity is a challenging health problem and its prevalence along with comorbidities are on the rise around the world. Ingestion of fish becomes trendy in daily meals. Recent research has shown that marine fish oil (FO) (found in tuna, sardines, and mackerel) may offer an alternative method for reducing obesity and problems associated with it. Marine FO rich in long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) and long-chain omega-6 polyunsaturated fatty acids (LC n-6 PUFA) plays an important role in reducing abnormalities associated with the metabolic syndrome and has a variety of disease-fighting properties, including cardioprotective activity, anti-atherosclerotic, anti-obesity, anti-cancer, anti-inflammatory activity. Studies in rodents and humans have indicated that LC n-3 PUFA potentially elicit a number of effects which might be useful for reducing obesity, including suppression of appetite, improvements in circulation, enhanced fat oxidation, energy expenditure, and reduced fat deposition. This review discusses the interplay between inflammation and obesity, and their subsequent regulation via the beneficial role of marine FO, suggesting an alternative dietary strategy to ameliorate obesity and obesity-associated chronic diseases.

Succinate is an important metabolite and a critical chemical with diverse applications in the food, pharmaceutical, and agriculture industries. Recent studies have demonstrated several protective or detrimental functions of succinate in diseases; however, the effect of succinate on lipid metabolism is still unclear. Here, we identified a role of succinate in nonobese nonalcoholic fatty liver disease (NAFLD). Specifically, the level of succinate is increased in the livers and serum of mice with hepatic steatosis. The administration of succinate promotes triglyceride (TG) deposition and hepatic steatosis by suppressing fatty acid oxidation (FAO) in nonobese NAFLD mouse models. RNA-Seq revealed that succinate suppressed fibroblast growth factor 21 (FGF21) expression. Then, the restoration of FGF21 was sufficient to alleviate hepatic steatosis and FAO inhibition induced by succinate treatment in vitro and in vivo. Furthermore, the inhibition of FGF21 expression and FAO mediated by succinate was dependent on the AMPK/PPARα axis. This study provides evidence linking succinate exposure to abnormal hepatic lipid metabolism and the progression of nonobese NAFLD.

We planned to explore the protective activities of extract of Phyllanthus emblica L. (EPE) on insulin resistance and metabolic disorders including hyperlipidemia, visceral obesity, and renal dysfunction in high-fat diet (HFD)-progressed T2DM mice. Mice treatments included 7 weeks of HFD induction followed by EPE, fenofibrate (Feno), or metformin (Metf) treatment daily for another 4-week HFD in HFD-fed mice. Finally, we harvested blood to analyze some tests on circulating glycemia and blood lipid levels. Western blotting analysis was performed on target gene expressions in peripheral tissues. The present findings indicated that EPE treatment reversed the HFD-induced increases in blood glucose, glycosylated HbA1C, and insulin levels. Our findings proved that treatment with EPE in HFD mice effectively controls hyperglycemia and hyperinsulinemia. Our results showed that EPE reduced blood lipid levels, including a reduction in blood triglyceride (TG), total cholesterol (TC), and free fatty acid (FFA); moreover, EPE reduced blood leptin levels and enhanced adiponectin concentrations. EPE treatment in HFD mice reduced BUN and creatinine in both blood and urine and lowered albumin levels in urine; moreover, EPE decreased circulating concentrations of inflammatory NLR family pyrin domain containing 3 (NLRP3) and kidney injury molecule-1 (KIM-1). These results indicated that EPE displayed antihyperglycemic and antihyperlipidemic activities but alleviated renal dysfunction in HFD mice. The histology examinations indicated that EPE treatment decreased adipose hypertrophy and hepatic ballooning, thus contributing to amelioration of lipid accumulation. EPE treatment decreased visceral fat amounts and led to improved systemic insulin resistance. For target gene expression levels, EPE enhanced AMP-activated protein kinase (AMPK) phosphorylation expressions both in livers and skeletal muscles and elevated the muscular membrane glucose transporter 4 (GLUT4) expressions. Treatment with EPE reduced hepatic glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) expressions to suppress glucose production in the livers and decreased phosphorylation of glycogen synthase kinase 3β (GSK3β) expressions to affect hepatic glycogen synthesis, thus convergently contributing to an antidiabetic effect and improving insulin resistance. The mechanism of the antihyperlipidemic activity of EPE involved a decrease in the hepatic phosphorylation of mammalian target of rapamycin complex C1 (mTORC1) and p70 S6 kinase 1 (S6K1) expressions to improve insulin resistance but also a reduction in hepatic sterol regulatory element binding protein (SREBP)-1c expressions, and suppression of ACC activity, thus resulting in the decreased fatty acid synthesis but elevated hepatic peroxisome proliferator-activated receptor (PPAR) α and SREBP-2 expressions, resulting in lowering TG and TC concentrations. Our results demonstrated that EPE improves insulin resistance and ameliorates hyperlipidemia in HFD mice.

Warm-blooded animals such as birds and mammals are able to protect stable body temperature due to various thermogenic mechanisms. These processes can be facultative (occurring only under specific conditions, such as acute cold) and adaptive (adjusting their capacity according to long-term needs). They can represent a substantial part of overall energy expenditure and, therefore, affect energy balance. Classical mechanisms of facultative thermogenesis include shivering of skeletal muscles and (in mammals) non-shivering thermogenesis (NST) in brown adipose tissue (BAT), which depends on uncoupling protein 1 (UCP1). Existence of several alternative thermogenic mechanisms has been suggested. However, their relative contribution to overall heat production and the extent to which they are adaptive and facultative still needs to be better defined. Here we focus on comparison of NST in BAT with thermogenesis in skeletal muscles, including shivering and NST. We present indications that muscle NST may be adaptive but not facultative, unlike UCP1-dependent NST. Due to its slow regulation and low energy efficiency, reflecting in part the anatomical location, induction of muscle NST may counteract development of obesity more effectively than UCP1-dependent thermogenesis in BAT.

Leptin can indirectly regulate fatty-acid metabolism and synthesis in muscle in vivo and directly in incubated muscle ex vivo. In addition, non-synonymous mutations in the bovine leptin gene (LEP) are associated with carcass intramuscular fat (IMF) content. However, the effects of LEP on lipid synthesis of adipocytes have not been clearly studied at the cellular level. Therefore, this study focused on bovine primary intramuscular preadipocytes to investigate the effects of LEP on the proliferation and differentiation of intramuscular preadipocytes, as well as its regulatory mechanism in lipid synthesis. The results showed that both the LEP and leptin receptor gene (LEPR) were highly expressed in IMF tissues, and their mRNA expression levels were positively correlated at different developmental stages of intramuscular preadipocytes. The overexpression of LEP inhibited the proliferation and differentiation of intramuscular preadipocytes, while interference with LEP had the opposite effect. Additionally, LEP significantly promoted the phosphorylation level of AMPKα by promoting the protein expression of CAMKK2. Meanwhile, rescue experiments showed that the increasing effect of AMPK inhibitors on the number of intramuscular preadipocytes was significantly weakened by the overexpression of LEP. Furthermore, the overexpression of LEP could weaken the promoting effect of AMPK inhibitor on triglyceride content and droplet accumulation, and prevent the upregulation of adipogenic protein expression (SREBF1, FABP4, FASN, and ACCα) caused by AMPK inhibitor. Taken together, LEP acted on the AMPK signaling pathway by regulating the protein expression of CAMKK2, thereby downregulating the expression of proliferation-related and adipogenic-related genes and proteins, ultimately reducing intramuscular adipogenesis.

Major depressive disorder has a complex, bidirectional relationship with metabolic dysfunction, but the neural correlates of this association are not well understood.

In this cross-sectional investigation, we used a 2-step discovery and confirmatory strategy utilizing 2 independent samples (sample 1: 288 participants, sample 2: 196 participants) to examine the association between circulating indicators of metabolic health (leptin and adiponectin) and brain structures in individuals with major depressive disorder.

We found a replicable inverse correlation between leptin levels and cortical surface area within essential brain areas responsible for emotion regulation, such as the left posterior cingulate cortex, right pars orbitalis, right superior temporal gyrus, and right insula (standardized beta coefficient range: -0.27 to -0.49, puncorrected < .05). Notably, this relationship was independent of C-reactive protein levels. We also identified a significant interaction effect of leptin levels and diagnosis on the cortical surface area of the right superior temporal gyrus (standardized beta coefficient = 0.26 in sample 1, standardized beta coefficient = 0.30 in sample 2, puncorrected < .05). We also observed a positive correlation between leptin levels and atypical depressive symptoms in both major depressive disorder groups (r = 0.14 in sample 1, r = 0.29 in sample 2, puncorrected < .05).

The inverse association between leptin and cortical surface area in brain regions that are important for emotion processing and leptin's association with atypical depressive symptoms support the hypothesis that metabolic processes may be related to emotion regulation. However, the molecular mechanisms through which leptin may exert these effects should be explored further.

Rabson-Mendenhall syndrome (RMS) is a rare autosomal, recessive disorder characterized by severe insulin resistance due to mutations in the insulin receptor (INSR) gene. This study aims to analyze the clinical features and gene mutations in RMS, which have not been extensively studied.

PubMed, Embase, the China National Knowledge Infrastructure, and Wanfang were searched for "Rabson-Mendenhall syndrome" or "Black acanthosis hirsutism insulin resistance syndrome."

A total of 42 cases from 33 articles were included. The body mass index ranged from 18.50 to 20.00 kg/m2 with an average of 16.00 kg/m2. There were no overweight (25.00∼29.90 kg/m2) or obese (≥30.00 kg/m2) patients. Acanthosis was present in 29 cases (29/42, 69.05%); growth retardation in 25 cases (25/42, 59.52%); dental anomalies including absence of teeth, crowding, and malocclusion in 23 cases (23/42, 54.76%); and hirsutism in 17 cases (17/42, 40.48%). The average glycosylated hemoglobin was 9.35%, and the average fasting blood-glucose was 8.44 mmol/L; the mean fasting insulin was 349.96 μIU/mL, and the average fasting C-peptide was 6.00 ng/mL. Diabetes was reported in 25 cases (25/33, 75.76%) all of which were diagnosed before 23 years old. All 42 patients had recorded gene mutations, with 22 patients (22/42, 52.38%) having ≥ 2 mutations and 20 cases (20/42, 47.62%) having only 1 mutation. No statistical differences were found in clinical features and laboratory parameters between patients with different mutations.

The study indicates that RMS should be considered in young patients with hyperinsulinemia, hyperglycemia with low weight, acanthosis nigricans, growth retardation, dental anomalies, and hirsutism.

Chronic liver disease (CLD) is a complex disease associated with profound dysfunction. Despite an incredible burden, the first and only pharmacotherapy for metabolic-associated steatohepatitis was only approved in March of this year, indicating a gap in the translation of preclinical studies. There is a body of preclinical work on the application of phosphodiesterase 4 inhibitors in CLD, none of these molecules have been successfully translated into clinical use.

To design therapies to combat CLD, it is essential to consider the dysregulation of other tissues that contribute to its development and progression. As such, proper therapies must combat this throughout the body rather than focusing only on the liver. To detail this, literature characterizing the pathogenesis of CLD was pulled from PubMed, with a particular focus placed on the role of PDE4 in inflammation and metabolism. Then, the focus is shifted to detailing the available information on existing PDE4 inhibitors.

This review gives a brief overview of some of the pathologies of organ systems that are distinct from the liver but contribute to disease progression. The demonstrated efficacy of PDE4 inhibitors in other human inflammatory diseases should earn them further examination for the treatment of CLD.

Lipodystrophy syndromes are rare diseases of genetic or acquired origin, characterized by quantitative and qualitative defects in adipose tissue. The metabolic consequences of lipodystrophy syndromes, such as insulin resistant diabetes, hypertriglyceridemia and hepatic steatosis, are frequently very difficult to treat, resulting in significant risks of acute and/or chronic complications and of decreased quality of life. The production of leptin by lipodystrophic adipose tissue is decreased, more severely in generalized forms of lipodystrophy, where adipose tissue is absent from almost all body fat depots, than in partial forms of the disease, where lipoatrophy affects only some parts of the body and can be associated with increased body fat in other anatomical regions. Several lines of evidence in preclinical and clinical models have shown that leptin replacement therapy could improve the metabolic complications of lipodystrophy syndromes. Metreleptin, a recombinant leptin analogue, was approved as an orphan drug to treat the metabolic complications of leptin deficiency in patients with generalized lipodystrophy in the USA or with either generalized or partial lipodystrophy in Japan and Europe. In this brief review, we will discuss the benefits and limitations of this therapy, and the new expectations arising from the recent development of a therapeutic monoclonal antibody able to activate the leptin receptor.

Ground-breaking discoveries have established 5'-AMP-activated protein kinase (AMPK) as a central sensor of metabolic stress in cells and tissues. AMPK is activated through cellular starvation, exercise and drugs by either directly or indirectly affecting the intracellular AMP (or ADP) to ATP ratio. In turn, AMPK regulates multiple processes of cell metabolism, such as the maintenance of cellular ATP levels, via the regulation of fatty acid oxidation, glucose uptake, glycolysis, autophagy, mitochondrial biogenesis and degradation, and insulin sensitivity. Moreover, AMPK inhibits anabolic processes, such as lipogenesis and protein synthesis. These findings support the notion that AMPK is a crucial regulator of cell catabolism. However, studies have revealed that AMPK's role in cell homeostasis might not be as unidirectional as originally thought. This Review explores emerging evidence for AMPK as a promoter of cell survival and an enhancer of anabolic capacity in skeletal muscle and adipose tissue during catabolic crises. We discuss AMPK-activating interventions for tissue preservation during tissue wasting in cancer-associated cachexia and explore the clinical potential of AMPK activation in wasting conditions. Overall, we provide arguments that call for a shift in the current dogma of AMPK as a mere regulator of cell catabolism, concluding that AMPK has an unexpected role in tissue preservation.

Exercise has many beneficial effects that provide health and metabolic benefits. Signaling molecules are released from organs and tissues in response to exercise stimuli and are widely termed exerkines, which exert influence on a multitude of intricate multi-tissue processes, such as muscle, adipose tissue, pancreas, liver, cardiovascular tissue, kidney, and bone. For the metabolic effect, exerkines regulate the metabolic homeostasis of organisms by increasing glucose uptake and improving fat synthesis. For the anti-inflammatory effect, exerkines positively influence various chronic inflammation-related diseases, such as type 2 diabetes and atherosclerosis. This review highlights the prospective contribution of exerkines in regulating metabolism, augmenting the anti-inflammatory effects, and providing additional advantages associated with exercise. Moreover, a comprehensive overview and analysis of recent advancements are provided in this review, in addition to predicting future applications used as a potential biomarker or therapeutic target to benefit patients with chronic diseases.

In the age of information technology and the additional computational search tools and software available, this systematic review aimed to identify potential therapeutic targets for obesity, evaluated in silico and subsequently validated in vivo. The systematic review was initially guided by the research question "What therapeutic targets have been used in in silico analysis for the treatment of obesity?" and structured based on the acronym PECo (P, problem; E, exposure; Co, context). The systematic review protocol was formulated and registered in PROSPERO (CRD42022353808) in accordance with the Preferred Reporting Items Checklist for Systematic Review and Meta-Analysis Protocols (PRISMA-P), and the PRISMA was followed for the systematic review. The studies were selected according to the eligibility criteria, aligned with PECo, in the following databases: PubMed, ScienceDirect, Scopus, Web of Science, BVS, and EMBASE. The search strategy yielded 1142 articles, from which, based on the evaluation criteria, 12 were included in the systematic review. Only seven these articles allowed the identification of both in silico and in vivo reassessed therapeutic targets. Among these targets, five were exclusively experimental, one was exclusively theoretical, and one of the targets presented an experimental portion and a portion obtained by modeling. The predominant methodology used was molecular docking and the most studied target was Human Pancreatic Lipase (HPL) (n = 4). The lack of methodological details resulted in more than 50% of the papers being categorized with an "unclear risk of bias" across eight out of the eleven evaluated criteria. From the current systematic review, it seems evident that integrating in silico methodologies into studies of potential drug targets for the exploration of new therapeutic agents provides an important tool, given the ongoing challenges in controlling obesity.

The high prevalence of metabolic syndrome is threatening the health of populations all over the world. Contemporary work demonstrates that high leptin concentration is directly related to the development of metabolic syndrome such as obesity, fatty liver diseases, type 2 diabetes mellitus and cardiovascular diseases. Anthocyanins are a widespread group of dietary polyphenols, which can ameliorate chronic diseases related to metabolic syndrome. In addition, anthocyanins can regulate the leptin pathway in chronic metabolic diseases, however the potential mechanism between anthocyanin and leptin is complex and elusive. In this review paper, we have evaluated the bioactivity of anthocyanins on the mediation of leptin level and the upstream and downstream pathways in chronic metabolic diseases. Anthocyanins could regulate the hypertrophy of adipose tissue, and the expression of leptin level via mediating TNF-α, C/EBP, PPAR, CREB and SREBP-1. Anthocyanins promoted the leptin sensitivity by increasing the level of leptin receptor, phosphorylation of JAK2/STAT3, PI3K/AKT, and additionally ameliorated metabolic disorder related outcome, including oxidative stress, inflammation, lipid accumulation, insulin resistance and the balance of gut microbiota. However, direct evidence of anthocyanins treatment on leptin signal transduction is still limited which calls for future molecular binding and gene regulation test.

Adipogenesis, defined as the development of mature adipocytes from stem cell precursors, is vital for the expansion, turnover and health of adipose tissue. Loss of adipogenic potential in adipose stem cells, or impairment of adipogenesis is now recognised as an underlying cause of adipose tissue dysfunction and is associated with metabolic disease. In this study, we sought to determine the role of AMP-activated protein kinase (AMPK), an evolutionarily conserved master regulator of energy homeostasis, in adipogenesis. Primary murine adipose-derived stem cells were treated with a small molecule AMPK activator (BI-9774) during key phases of adipogenesis, to determine the effect of AMPK activation on adipocyte commitment, maturation and function. To determine the contribution of the repression of lipogenesis by AMPK in these processes, we compared the effect of pharmacological inhibition of acetyl-CoA carboxylase (ACC). We show that AMPK activation inhibits adipogenesis in a time- and concentration-dependent manner. Transient AMPK activation during adipogenic commitment leads to a significant, ACC-independent, repression of adipogenic transcription factor expression. Furthermore, we identify a striking, previously unexplored inhibition of leptin gene expression in response to both short-term and chronic AMPK activation irrespective of adipogenesis. These findings reveal that in addition to its effect on adipogenesis, AMPK activation switches off leptin gene expression in primary mouse adipocytes independently of adipogenesis. Our results identify leptin expression as a novel target of AMPK through mechanisms yet to be identified.

Diabetes mellitus (DM) is a highly prevalent disease worldwide, estimated to affect 1 in every 11 adults; among them, 90-95% of cases are type 2 diabetes mellitus. This is partly attributed to the surge in the prevalence of obesity, which has reached epidemic proportions since 2008. In these patients, cardiovascular (CV) risk stands as the primary cause of morbidity and mortality, placing a substantial burden on healthcare systems due to the potential for macrovascular and microvascular complications. In this context, leptin, an adipocyte-derived hormone, plays a fundamental role. This hormone is essential for regulating the cellular metabolism and energy balance, controlling inflammatory responses, and maintaining CV system homeostasis. Thus, leptin resistance not only contributes to weight gain but may also lead to increased cardiac inflammation, greater fibrosis, hypertension, and impairment of the cardiac metabolism. Understanding the relationship between leptin resistance and CV risk in obese individuals with type 2 DM (T2DM) could improve the management and prevention of this complication. Therefore, in this narrative review, we will discuss the evidence linking leptin with the presence, severity, and/or prognosis of obesity and T2DM regarding CV disease, aiming to shed light on the potential implications for better management and preventive strategies.

5´-Adenosine monophosphate (AMP)-activated protein kinase (AMPK), a cellular energy sensor, is an essential enzyme that helps cells maintain stable energy levels during metabolic stress. The hypothalamus is pivotal in regulating energy balance within the body. Certain neurons in the hypothalamus are sensitive to fluctuations in food availability and energy stores, triggering adaptive responses to preserve systemic energy equilibrium. AMPK, expressed in these hypothalamic neurons, is instrumental in these regulatory processes. Hypothalamic AMPK activity is modulated by key metabolic hormones. Anorexigenic hormones, including leptin, insulin, and glucagon-like peptide 1, suppress hypothalamic AMPK activity, whereas the hunger hormone ghrelin activates it. These hormonal influences on hypothalamic AMPK activity are central to their roles in controlling food consumption and energy expenditure. Additionally, hypothalamic AMPK activity responds to variations in glucose concentrations. It becomes active during hypoglycemia but is deactivated when glucose is introduced directly into the hypothalamus. These shifts in AMPK activity within hypothalamic neurons are critical for maintaining glucose balance. Considering the vital function of hypothalamic AMPK in the regulation of overall energy and glucose balance, developing chemical agents that target the hypothalamus to modulate AMPK activity presents a promising therapeutic approach for metabolic conditions such as obesity and type 2 diabetes mellitus.

The link between cellular exposure to fatty acid species and toxicity phenotypes remains poorly understood. However, structural characterization and functional profiling of human plasma free fatty acids (FFAs) analysis has revealed that FFAs are located either in the toxic cluster or in the cluster that is transcriptionally responsive to lipotoxic stress and creates genetic risk factors. Genome-wide short hairpin RNA screen has identified more than 350 genes modulating lipotoxicity. Hypertrophic adipocytes in obese adipose are both unable to expand further to store excess lipids in the diet and are resistant to the antilipolytic action of insulin. In addition to lipolysis, the inability of packaging the excess lipids into lipid droplets causes circulating fatty acids to reach toxic levels in non-adipose tissues. Deleterious effects of accumulated lipid in non-adipose tissues are known as lipotoxicity. Although triglycerides serve a storage function for long-chain non-esterified fatty acid and their products such as ceramide and diacylglycerols (DAGs), overloading of palmitic acid fraction of saturated fatty acids (SFAs) raises ceramide levels. The excess DAG and ceramide load create harmful effects on multiple organs and systems, inducing chronic inflammation in obesity. Thus, lipotoxic inflammation results in β cells death and pancreatic islets dysfunction. Endoplasmic reticulum stress stimuli induce lipolysis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and extracellular signal-regulated kinase (Erk) 1/2 signaling in adipocytes. However, palmitic acid-induced endoplasmic reticulum stress-c-Jun N-terminal kinase (JNK)-autophagy axis in hypertrophic adipocytes is a pro-survival mechanism against endoplasmic reticulum stress and cell death induced by SFAs. Endoplasmic reticulum-localized acyl-coenzyme A (CoA): glycerol-3-phosphate acyltransferase (GPAT) enzymes are mediators of lipotoxicity, and inhibiting these enzymes has therapeutic potential for lipotoxicity. Lipotoxicity increases the number of autophagosomes, which engulf palmitic acid, and thus suppress the autophagic turnover. Fatty acid desaturation promotes palmitate detoxification and storages into triglycerides. As therapeutic targets of glucolipotoxicity, in addition to caloric restriction and exercise, there are four different pharmacological approaches, which consist of metformin, glucagon-like peptide 1 (GLP-1) receptor agonists, peroxisome proliferator-activated receptor-gamma (PPARγ) ligands thiazolidinediones, and chaperones are still used in clinical practice. Furthermore, induction of the brown fat-like phenotype with the mixture of eicosapentanoic acid and docosahexaenoic acid appears as a potential therapeutic application for treatment of lipotoxicity.

The biological clocks of the circadian timing system coordinate cellular and physiological processes and synchronize them with daily cycles. While the central clock in the suprachiasmatic nucleus (SCN) is mainly synchronized by the light/dark cycles, the peripheral clocks react to other stimuli, including the feeding/fasting state, nutrients, sleep-wake cycles, and physical activity. During the disruption of circadian rhythms due to genetic mutations or social and occupational obligations, incorrect arrangement between the internal clock system and environmental rhythms leads to the development of obesity. Desynchronization between the central and peripheral clocks by altered timing of food intake and diet composition leads to uncoupling of the peripheral clocks from the central pacemaker and to the development of metabolic disorders. The strong coupling of the SCN to the light-dark cycle creates a situation of misalignment when food is ingested during the "wrong" time of day. Food-anticipatory activity is mediated by a self-sustained circadian timing, and its principal component is a food-entrainable oscillator. Modifying the time of feeding alone greatly affects body weight, whereas ketogenic diet (KD) influences circadian biology, through the modulation of clock gene expression. Night-eating behavior is one of the causes of circadian disruption, and night eaters have compulsive and uncontrolled eating with severe obesity. By contrast, time-restricted eating (TRE) restores circadian rhythms through maintaining an appropriate daily rhythm of the eating-fasting cycle. The hypothalamus has a crucial role in the regulation of energy balance rather than food intake. While circadian locomotor output cycles kaput (CLOCK) expression levels increase with high-fat diet-induced obesity, peroxisome proliferator-activated receptor-alpha (PPARα) increases the transcriptional level of brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like 1 (BMAL1) in obese subjects. In this context, effective timing of chronotherapies aiming to correct SCN-driven rhythms depends on an accurate assessment of the SCN phase. In fact, in a multi-oscillator system, local rhythmicity and its disruption reflects the disruption of either local clocks or central clocks, thus imposing rhythmicity on those local tissues, whereas misalignment of peripheral oscillators is due to exosome-based intercellular communication.Consequently, disruption of clock genes results in dyslipidemia, insulin resistance, and obesity, while light exposure during the daytime, food intake during the daytime, and sleeping during the biological night promote circadian alignment between the central and peripheral clocks. Thus, shift work is associated with an increased risk of obesity, diabetes, and cardiovascular diseases because of unusual eating times as well as unusual light exposure and disruption of the circadian rhythm.

Diabetic cardiomyopathy (DCM) is a chronic microvascular complication of diabetes that is generally defined as ventricular dysfunction occurring in patients with diabetes and unrelated to known causes. Several mechanisms have been proposed to contribute to the occurrence and persistence of DCM, in which oxidative stress and autophagy play a non-negligible role. Diabetic cardiomyopathy is involved in a variety of physiological and pathological processes. The 5' adenosine monophosphate-activated protein kinase/nuclear factor-erythroid 2-related factor 2 (AMPK/Nrf2) are expressed in the heart, and studies have shown that asiaticoside (ASI) and activated AMPK/Nrf2 have a protective effect on the myocardium. However, the roles of ASI and AMPK/Nrf2 in DCM are unknown. The intraperitoneal injection of streptozotocin (STZ) and high-fat feed were used to establish the DCM models in 100 C57/BL mice. Asiaticoside and inhibitors of AMPK/Nrf2 were used for intervention. Cardiac function, oxidative stress, and autophagy were measured in mice. DCM mice displayed increased levels of oxidative stress while autophagy levels declined. In addition, AMPK/Nrf2 was activated in DCM mice with ASI intervention. Further, we discovered that AMPK/Nrf2 inhibition blocked the protective effect of ASI by compound C and treatment with ML-385. The present study demonstrates that ASI exerts a protective effect against DCM via the potential activation of the AMPK/Nrf2 pathway. Asiaticoside is a potential therapeutic target for DCM.