Neuropeptide Y (NPY) is a key regulator of energy homeostasis, acting through various receptor subtypes in both central and peripheral systems. Increasing interest has been directed toward exploiting NPY as a pharmacological target in obesity. While the orexigenic role of NPY in the hypothalamus is well established, its downstream effects on peripheral metabolism remain less defined, particularly when perturbations to the system are introduced. Previously, we observed that female mice with limbic NPY-Y1 receptor gene (Npy1r) knockout (KO) under different dietary conditions (standard, SD, or high-fat diet, HFD) accumulated more subcutaneous white adipose tissue (WAT) compared to wild-type in the absence of gonadal hormones, despite no changes in food intake. To deepen the mechanisms underlying these effects, we conducted molecular analyses on WAT of these mice. We found that Npy gene expression was upregulated in WAT of HFD-fed mice, regardless of genotype. However, NPY peptide levels were reduced in both KO and HFD groups, suggesting post-transcriptional regulation of NPY under metabolic stress. NPY-Y2 receptor gene (Npy2r) expression in WAT was significantly increased in both KO and HFD while Npy1r expression in WAT remained unchanged across groups. Genes involved in WAT metabolism were similarly upregulated in both KO and HFD mice, indicating that limbic Npy1r KO mimics some of the metabolic effects induced by HFD. Correlation analysis suggests that dysregulated NPY signalling may promote increased lipid storage and reduce energy expenditure. Overall, these findings highlight the complex interplay between central and peripheral NPY signalling emphasizing the importance of caution when investigating therapeutic strategies targeting single NPY receptors. Overall, these findings highlight the complex interplay between central Npy1r signalling and peripheral adipose tissue regulation. They also emphasize the importance of caution when investigating new therapeutic strategies targeting single NPY receptors, as central interventions may provoke maladaptive metabolic responses in peripheral tissues.

Bombesin receptor-activated protein homolog deficiency reduces food intake and alleviates metabolic dysfunction in high-fat diet treated mice.

Aerobic exercise training (AET) and numerous dietary interventions, including nitrate and resveratrol supplementation, display overlapping mechanisms affecting mitochondrial bioenergetics and metabolism in diverse tissues. However, it remains unclear if a combination of these interventions results in additive benefits for the prevention of obesity-related co-morbidities. To investigate this, C57Bl/6N mice consumed a high-fat diet and remained sedentary (HFD) or performed AET for 6 weeks in the absence (HFD+AET) or presence of nitrate+resveratrol supplementation (HFD+AET+NR). As expected, AET attenuated body weight gain, reduced adipocyte cross-sectional area and markers of cellular stress/inflammation within white adipose tissue, and increased mitochondrial respiratory capacity and decreased lipid content within skeletal muscle independent of supplementation. While AET alone was sufficient to improve glucose tolerance, the addition of +NR provided modest liver-specific enhancements including increased mitochondrial respiratory capacity, reduced reactive lipid accumulation, and a unique proteomic signature associated with altered amino acid metabolism, corresponding to further reductions in systemic fasting blood glucose levels. These data suggest that while AET remains a primary lifestyle intervention to drive metabolic improvements during high-fat feeding, targeted dietary supplementation may provide tissue-specific enhancements, particularly within the liver, that complement exercise adaptations.

A transcriptionally distinct population of human adipocytes with end-of-trajectory signature (hEOS) emerges during obesity to drive maladaptive inflammation.

Erchen decoction promotes inguinal white adipose tissue browning via the M2 macrophage-sympathetic axis to ameliorate obesity in mice.

Obesity is characterised by pathological alterations in visceral white adipose tissue (vWAT) that may contribute to thedevelopment of type 2 diabetes (T2D). While microRNAs (miRNAs) are key post-transcriptional regulators, comprehensive human vWAT profiling across metabolic states remains limited. This study characterised vWAT miRNA expression in lean, obese and obese+T2D individuals to identify obesity-driven regulatory networks associated with metabolic dysfunction. Deep miRNA sequencing was performed on vWAT samples from a discovery cohort comprising lean controls and individuals with obesity (with and without T2D). Findings were validated via RT-qPCR in an independent replication cohort. Differentially expressed miRNAs were bioinformatically integrated with matched mRNA transcriptomic data to construct putative functional regulatory associations and identify enriched pathways underlying metabolic impairment. The dominant transcriptomic signal was driven by obesity rather than T2D status, with substantial overlap between obese subgroups in principal component analyses. miR-141-3p, miR-200b-3p, miR-12 136 and miR-585-3p showed consistent differential expression associated with obesity. miR-141-3p and miR-200b-3p were upregulated and inversely associated with metabolic stress-related genes, including TF and FBXO32. Integrated miRNA-mRNA analyses revealed putative regulatory associations involving inflammation, lipid metabolism, insulin signalling and iron homeostasis. These associations were robust across progressive covariate adjustment models for age and sex. This study provides a comprehensive characterisation of the vWAT miRNA landscape predominantly shaped by obesity, with T2D contributing comparatively subtle additional variation. We identified putative miRNA-mRNA regulatory associations that may contribute to pathological adipose tissue dysfunction. These findings highlight candidate molecular regulators worthy of further functional investigation in the context of obesity and T2D.

The selection of the appropriate energy substrate under different physiological conditions is a key aspect of the energy metabolism homeostasis. We here show that Nos1 (nitric oxide synthase 1)-expressing cells in the paraventricular hypothalamic nucleus (PVH) serve as a pivotal node for controlling whole-body fat consumption in male mice. Nos1 neurons account for ~30% of PVH neurons that convey signals via polysynaptic pathways to individual peripheral tissues, including skeletal muscle and brown (BAT) and white (WAT) adipose tissues. Activation of these Nos1 neurons in the PVH area induces WAT lipolysis and fat oxidation in other peripheral tissues via the sympathetic nervous system, thereby increasing whole-body fat consumption. Inhibition of these neurons abolishes the increase in fat consumption during the light period, whereas long-term silencing lead to obesity independent of energy intake. These neurons are also necessary for cold-induced thermogenesis in BAT and the rapid increase in fat consumption elicited by food deprivation or other stressors. Nos1 neurons in the PVH area are therefore essential for controlling fat consumption and energy homeostasis.

Transcriptomics-driven drug screening identifies BRD-K78062244 in promoting white adipose tissue browning.

The effects of long-term aerobic exercise on prostate cancer-induced adipose tissue wasting: Browning to the rescue?

To investigate the mechanism by which electroacupuncture (EA) at "Zusanli" (ST36) ameliorates the impairment of feeding behavior and gastric vagal afferent signaling induced by short-term high-fat diet (HFD) exposure. The study comprised two parts. In part 1, 42 SPF male C57BL/6J mice were randomly divided into a normal diet (ND) group (n=14) and an HFD group (n=28). After 4 weeks, HFD-fed mice were subdivided into an HFD group and an EA group (n=14 each). The EA group received EA at bilateral "Zusanli" (ST36). Stimulation parameters were:2 mA, 2 Hz/15 Hz, 20 min/session, once daily, 6 sessions/week for 2 consecutive weeks. Body weight was recorded weekly. After the intervention, 24 h food intake was measured. Liver wet weight, inguinal white adipose tissue (iWAT) wet weight, and epididymal white adipose tissue (eWAT) wet weight were recorded. Gastric emptying rate was assessed using the phenol red meal test. Serum cholecystokinin (CCK) content was measured by ELISA. Protein expressions of protein gene product 9.5 (PGP9.5) and calcitonin gene-related peptide (CGRP) in the gastric antrum were evaluated by Western blot. The co-expression density index of PGP9.5 and CGRP in the gastric antrum and c-Fos expression levels in the nodose ganglion (NG) were detected by immunofluorescence staining. In part 2, another 32 SPF male C57BL/6J mice were fed an HFD for 4 weeks and then randomly divided into 4 groups (n=8 each):sham operation group, sham + EA group, vagotomy (resection of the gastric vagal branches) group, and vagotomy + EA group. The acupoint and intervention parameters were the same as above. Body weight, 24 h food intake, liver wet weight, iWAT wet weight, eWAT wet weight, the co-expression of PGP9.5 and CGRP in the gastric antrum, and the number of c-Fos positive neurons in the NG were measured. Compared to the ND group, 4-week HFD feeding increased body weight, liver wet weight, and adipose tissue (iWAT and eWAT) wet weights, while decreased gastric emptying rate and serum CCK levels(P<0.05). The relative protein expressions of both PGP9.5 and CGRP in the gastric antrum were down-regulated(P<0.05). Meanwhile, the co-expression density index of PGP9.5 and CGRP in the gastric antrum was reduced(P<0.05). The number of c-Fos positive neurons in the NG decreased in HFD-fed mice(P<0.05). Compared to the HFD group, EA treatment reduced body weight, 24 h food intake, liver wet weight, and adipose tissue (iWAT and eWAT) wet weights(P<0.05). EA also increased gastric emptying rate and serum CCK levels(P<0.05). Moreover, EA up-regulated the relative protein expressions of PGP9.5 and CGRP as well as their co-expression density index in the gastric antrum(P<0.05). Finally, EA increased the number of c-Fos positive neurons in the NG(P<0.05). In the vagotomy experiment, compared with the sham operation group, the sham{L-End} +{L-End} EA group showed a significant decrease in body weight, food intake, liver wet weight, adipose tissue wet weight (P<0.05). After gastric branch vagotomy, however, the regulatory effects of EA on body weight, food intake, liver wet weight, and other indicators were weakened. Similarly, after surgery EA did not exert a significant modulatory effect on the co-expression level of PGP9.5 and CGRP in the gastric antrum or on the expression of c-Fos-positive neurons in the NG. Short-term HFD leads to desensitization of gastric vagal afferent signaling, manifested as impairment of local gastric vagal sensory nerves and a decrease in the number of activated neurons in the NG. EA can suppress food intake by repairing gastric vagal afferent signaling.

Administration of ciliary neurotrophic factor (CNTF) reduces food intake and body weight in both humans and experimental animals, where it also ameliorates hyperglycemia, hyperinsulinemia, and dyslipidemia. To exert its anti-obesogenic and anti-diabetogenic effects, CNTF targets brain feeding centers as well as multiple peripheral organs inducing the phosphorylation of the transcription factor signal transducer and activator of transcription 3 (p-STAT3). However, data showing which peripheral cytotypes are specifically targeted by exogenous CNTF invivo in metabolically relevant organs are currently lacking. Here, we first evaluated the gene expression levels of the subunits of the tripartite CNTF receptor (Cntfr) complex, that is, the Cntfrα, the leukemia inhibitory factor receptor β (Lifrβ) and the glycoprotein 130 (gp130), by quantitative real-time PCR in metabolically relevant organs of adult male mice: gastrointestinal (GI) tract, pancreas, liver, visceral and subcutaneous white (WAT) and interscapular brown adipose tissue (iBAT), skeletal muscle and the sciatic nerve. We then quantified p-STAT3 by Western blotting in these organs after intraperitoneal administration of CNTF (0.3 mg/kg) or saline. Finally, we mapped CNTF-responsive cells by immunohistochemistry, followed by morphometric quantification and confocal microscopy in both CNTF- and saline-treated mice. Lifrβ and gp130 were ubiquitously detected across all the investigated organs; the Cntfrα showed the highest expression levels in the skeletal muscle, sciatic nerve, and iBAT, whereas it was found to be expressed to a lesser extent in the other sites. Administration of CNTF led to a significant increase of p-STAT3/STAT3 protein ratio in all organs examined, except the duodenum, and induced a distinctive pattern of cell nuclear p-STAT3 immunoreactivity. Notably, along the analyzed GI tract, CNTF induced nuclear STAT3 phosphorylation in neurons of the submucosal and myenteric plexuses of the enteric nervous system and in contractile cells of the muscularis externa, where the response peaked in the mesenteric gut and colon. In the pancreas, CNTF triggered a higher activation within the endocrine component compared to the exocrine parenchyma. In the liver, CNTF induced STAT3 phosphorylation not only in parenchymal cells but also in sinusoids and resident macrophages. The cytokine activated p-STAT3 in subcutaneous and visceral white adipocytes, but also in brown adipocytes, with a prominent response observed in the beige subcutaneous adipocytes; adipose-resident macrophages and endothelial cells of numerous blood vessels were also CNTF-responsive. Lastly, in skeletal muscle, a major site for glucose/lipid utilization, CNTF induced widespread nuclear p-STAT3 immunoreactivity in muscle fibers and in connective and Schwann cells of the peripheral nerves, including the sciatic nerve, supplying the gastrocnemius. In conclusion, our data indicate that CNTF acts across diverse cytotypes within metabolically relevant organs and tissues, likely fostering its peripheral metabolic effects through this cellular heterogeneity.

Roux-en-Y gastric bypass (RYGB) is a highly effective therapy for obesity and type 2 diabetes mellitus (T2DM), but its underlying mechanisms, particularly regarding adipose tissue remodeling, remain incompletely understood. This study investigated the hypothesis that RYGB induces a phenotypic shift in white adipose tissue (WAT) towards a brown-like (beige) state, which contributes to its systemic metabolic benefits. An obese T2DM model was established in C57BL/6J mice using a high-fat diet and low-dose streptozotocin. Mice were allocated to control (CON), sham-operated (SHAM), or RYGB groups. Metabolic parameters were monitored for 8 weeks post-surgery. Terminal analyses included body composition assessment via micro-CT, plasma lipid profiling, and histological evaluation of liver and multiple adipose depots (epididymal, inguinal, perirenal, and brown adipose tissue). RYGB induced sustained weight loss, normalized glycemia, improved insulin sensitivity, and corrected dyslipidemia. Body composition analysis revealed a preferential reduction in visceral and subcutaneous fat mass, with lean mass preserved. Histologically, RYGB markedly alleviated hepatic steatosis. Crucially, RYGB induced a profound remodeling of WAT, characterized by a significant reduction in adipocyte size in both epididymal and inguinal depots, indicating improved adipose tissue health. Concomitantly, brown adipose tissue exhibited a reversal of obesity-associated "whitening," displaying a more active morphology with smaller lipid droplets. Beyond its established effects on weight and metabolism, RYGB induces morphological changes in white adipose tissue consistent with improved metabolic health. This structural and phenotypic reprogramming of fat depots likely represents a key cellular mechanism underpinning the surgery's potent anti-diabetic and hepatoprotective effects. Our findings highlight adipose tissue plasticity as a central therapeutic target of RYGB. Not applicable.

Obesity is a global metabolic challenge that leads to excessive fat accumulation and adipose tissue dysfunction due to the disruption of the balance between energy intake and consumption. This study focuses on whether Erchen Decoction promotes high-fat diet-induced white fat browning in obese rats through the SP1/SREBP/UCP1 signaling pathway, thereby improving obesity. Male SD rats were fed a high-fat diet to establish an obesity model, and were randomly divided into the High-fat diet (HFD) group, Erchen Decoction low dose, medium dose, high dose groups, and high dose + SP1 inhibitor group. Rats fed a normal diet served as the control group. TC, TG, LDL-C and HDL-C were detected by an automatic biochemical analyzer; the morphology of adipose tissue was observed with HE staining; the expression of SP1, SREBP and UCP1 in adipose tissue was detected with immunofluorescence staining; the mRNA and protein expression levels of SP1, SREBP, UCP1, PPA γ, PGC-1α, p-p65, Fass and ACC in white adipose tissue were detected with Real-time PCR and Western blot respectively. Each dose group of Erchen Decoction and the HD-SP1i group could effectively improve the body weight, blood lipids, and fat tissue morphology of obese rats. After the intervention of Erchen Decoction and HD-SP1i, the expressions of UCP1 and PGC-1α in rat adipose tissue cells were up-regulated, while the expressions of SP1, SREBP, PPA γ, p-p65, Fass, and ACC were inhibited. Obesity is a significant global health challenge closely linked to metabolic disorders. According to Traditional Chinese Medicine (TCM) theory, it is often understood as stemming from spleen deficiency leading to the accumulation of phlegm-dampness. Erchen Decoction, a classic TCM formula, achieves its therapeutic effects through the synergistic action of its herbal components, which collectively strengthen the spleen, resolve phlegm, and eliminate dampness. This study demonstrates that Erchen Decoction effectively reduces body weight, improves dyslipidemia, and alleviates pathological changes in adipose tissue in obese rats. The findings indicate that the decoction promotes a "browning" tendency in white adipose tissue, as evidenced by the upregulation of thermogenic markers UCP1 and PGC-1α, and the downregulation of key lipogenic factors SP1, SREBP, Fas, and ACC. These observations suggest that the anti-obesity effects of Erchen Decoction may be mediated through the modulation of the SP1/SREBP/UCP1 signaling pathway, which induces white adipose tissue browning and suppresses lipogenesis. This study provides novel molecular insights into the anti- obesity mechanism of Erchen Decoction, enriching the evidence base for TCM in the treatment of metabolic diseases. Future research should aim to obtain direct histological evidence of UCP1 expression and the formation of multilocular adipocytes, and further explore the effects of the formula on related cellular stress pathways. Erchen Decoction may activate the SP1/SREBP/UCP1 signaling pathway and induce browning tendency in white adipose tissue, thereby exerting weight loss.

Adipocyte death is a key event in the development of white adipose tissue (WAT) inflammation, a major driver of obesity-associated metabolic dysfunction. Receptor-interacting protein kinase 3 (RIPK3) mediates necroptosis, a recently discovered mode of regulated necrosis. Necroptosis has been implicated in several inflammatory pathologies; however, the role of adipocyte necroptosis in obesity remains unclear. In the present study, we sought to investigate the role of adipocyte RIPK3 in obesity and glucose homeostasis. We demonstrated that necroptotic signalling was upregulated in WAT of mice with diet-induced obesity and was associated with body-mass index in human WAT. We also demonstrated that caspase-8, a central regulator of apoptosis, suppresses adipocyte necroptosis both in vitro and in vivo. Adipocyte-specific deletion of caspase-8 in mice reduced adiposity compared to control mice. This difference was not observed with concomitant global deletion of RIPK3. Furthermore, adipocyte-specific deletion of the RIPK3 receptor-interacting protein homotypic interaction motif (RHIM), which is required for necroptotic induction, did not influence weight gain, adiposity, or glucose homeostasis in mice with diet-induced obesity. Caspase-8 knockdown by siRNA or pharmacological inhibition in 3T3-L1 adipocytes suppressed adipogenesis, which may be independent of adipocyte Ripk3. Collectively, our findings suggest that adipocyte RIPK3 RHIM does not play a critical role in obesity and glucose homeostasis. Alternatively, we provide further evidence that caspase-8 plays an essential role in adipocyte differentiation, offering insight into the molecular mechanisms underlying obesity and metabolic dysfunction.

Curcuma zedoaria may serve as a promising material for preventing and/or improving lifestyle-related diseases, considering its known in vitro adiponectin-elevating effects. Here, we aimed to determine the effects of a C. zedoaria ethanol extract (CZE) on high-fat diet (HFD)-induced obesity in C57BL/6N mice, to elucidate its effects on lifestyle-related diseases. CZE treatment with an HFD (HFD-CZE) reduced liver weight, subcutaneous fat, mesenteric fat, and hepatic lipid accumulation, along with alleviating the levels of plasma triglyceride, total-cholesterol, low density lipoprotein-cholesterol, aspartate aminotransferase, and alanine aminotransferase relative to those in the HFD group. Decreased mRNA expressions of Tnfa and Il6 and increased mRNA expression of adiponectin were observed in epididymal white adipose tissue of the HFD-CZE group. CZE also reduced hepatic Tnfa and Fabp4 mRNA expressions. Thus, C. zedoaria may ameliorate obesity-induced whole-body inflammation, potentially aiding in preventing and improving obesity and subsequent lifestyle-related diseases.

Lipid metabolism is closely related to aging, and its disorders can lead to obesity, insulin resistance, cardiovascular diseases, and various other conditions. The accumulation of lipids caused by increased lipid synthesis is key in the development of obesity, but the molecular mechanisms of increased lipid synthesis remain to be thoroughly studied, especially in the context of aging. In this work, we used in vivo and in vitro models to demonstrate that the long noncoding RNA Lncbate1 contributes to obesity by promoting lipid accumulation. Specifically, Lncbate1 increases lipid synthesis by downregulating the expression of miR-455-5p to increase the expression of the lipid synthesis gene ACSS1. Our findings highlighted Lncbate1 as a likely target for the intervention of aging-related obesity.

Ambra1 is essential for fasting-induced lipolysis via ATGL translocation to lipid droplets.

Nicotinamide enhances lipid deposition and thermogenesis in goat brown adipocytes.

Adiponectin is the most abundant hormone in the circulation. Plasma adiponectin decreases in obesity but increases in leanness, including during caloric restriction (CR) in animals and humans. In obesity, adiponectin deficiency promotes cardiometabolic dysfunction. In contrast, the roles of adiponectin in CR, when it is at its highest, are largely unknown. To address this, we studied global adiponectin knockout (KO) in male and female mice fed either ad libitum (AL) or a 30% CR diet from 9–13 weeks of age. We show that adiponectin KO did not alter CR effects on body mass, body composition, or energy expenditure. However, KO unexpectedly decreased blood glucose levels during CR, both with fasting and following an oral glucose challenge. This is opposite to the effects of adiponectin deficiency during AL feeding or obesity and occurred without changes in insulin concentrations or sensitivity. Moreover, adiponectin KO augmented CR-induced increases in plasma fatty acids in both sexes and, in males only, impaired systemic triglyceride clearance on both AL and CR diets. These effects on lipid metabolism were associated with sex- and diet-specific KO effects on white adipose tissue, including altered adipocyte size and expression of key regulators of adipocyte lipid metabolism. Indirect calorimetry further revealed that adiponectin KO alters the shifts between carbohydrate and lipid utilization that occur during transitions between fed and fasted states. To determine potential molecular mechanisms, we investigated effects of adiponectin KO on the liver, a major adiponectin target that plays key roles entraining metabolism to nutritional state. Hepatic transcriptomics revealed that, in both sexes, adiponectin KO upregulates sterol and fatty acid synthesis genes under AL while increasing amino acid catabolic genes during CR. However, the latter occurred without altering plasma or hepatic amino acid concentrations. Together, our findings suggest that adiponectin exerts sexually dimorphic effects on glucose, lipid, and amino acid metabolism during CR, in whole or in part through effects on the liver. Thus, the roles adiponectin in CR differ markedly from its widely reported functions in obesity, insulin resistance, and other pathological states.

Synbiotics and antioxidants synergistically attenuate disease progression in metabolic dysfunction-associated steatotic liver disease.