Somatostatin (Sst) is an inhibitory regulator of many hormones. The prenatal environment impacts an offspring's risk to type 2 diabetes in adulthood. However, the effect of maternal Sst deficiency on glucose and insulin metabolism in offspring and metabolic disease risk in their adult life has been poorly understood. The study was to investigate the impact of a lack of maternal Sst exposure in mouse male and female offspring on diet-induced changes in glucose metabolism and adiposity. Sst knockout offspring, SstKO born to the Sst-heterozygous dams or SstKO-MSD born to the Sst-homozygous dams were fed either a regular diet (CD) or a high-fat diet (HFD) at 3-week-old for 15 weeks. Body weight and blood glucose levels were monitored. Glucose and insulin tolerance tests were performed. Plasma hormone levels and gene expression in the hypothalamus were investigated. The results demonstrated that only male SstKO-MSD offspring developed obesity accompanied by severe insulin and leptin resistance after HFD challenge. Insulin secretion was reduced in both basal and oral glucose-challenged conditions in the CD-fed male SstKO-MSD mice. A reduced ratio of islet area to pancreas area was noted in SstKO-MSD mice in both sexes. Plasma levels of glucagon, Glp1 and Pyy were elevated in both male and female SstKO and SstKO-MSD mice. mRNA expression of leptin receptor, FoxO1, Npy and Agrp was downregulated in male SstKO-MSD mice. These results demonstrate that a lack of fetal somatostatin exposure impairs the islet development in offspring and increases risk of obesity, insulin resistance and leptin resistance later in life.

This study aimed to evaluate the long-term effects of hormone therapies on the body composition, adipokines and metabolic parameters of adult men with congenital hypogonadotropic hypogonadism (CHH).

Sixty-six patients with CHH and 21 healthy controls were recruited. Patients were divided into untreated (n = 33) and treated (n = 33) groups based on hormone therapy history. Body composition was assessed using dual-energy X-ray absorptiometry (DXA), and adipokines and metabolic parameters were measured in all participants.

Compared to the healthy control group, patients in the treated group had lower serum testosterone levels (p < 0.001), increased body fat percentage (BFP) and visceral adipose tissue (VAT) volume, decreased lean soft tissue (LST) and bone mineral content (BMC) (p < 0.05), increased serum leptin levels accompanied by decreased adiponectin (ADP) (p < 0.05), higher HOMA-IR with lower QUICKI (p < 0.05). Compared to the untreated group, patients in the treated group (therapy duration 4.8 ± 2.3 years) had higher serum testosterone levels (p < 0.001), decreased BFP and VAT volume, increased LST and BMC (p < 0.05), decreased serum leptin levels (p < 0.001), and decreased HOMA-IR accompanied by increased QUICKI (p < 0.05). Among them, VAT volume, LST, BMC, HOMA-IR and QUICKI reached healthy control levels (p > 0.05). Multiple stepwise linear regression analysis showed serum testosterone levels were negatively correlated with BFP (β = -0.564, p < 0.001) and VAT volume (β = -0.260, p = 0.045), positively correlated with LST (β = 0.305, p = 0.018) and BMC (β = 0.423, p = 0.001). Serum testosterone levels were independently negatively correlated with leptin levels (β = -0.277, p = 0.004).

Patients with untreated CHH had impaired body composition, adipokines and metabolic parameters. While hormone therapies can improve body composition and glucolipid metabolism in patients with CHH, this imperfect treatment does not fully rescue body composition abnormalities when compared to healthy individuals. Abnormal metabolic parameters in patients with CHH are associated with increased fat mass and abnormal serum leptin level. Serum testosterone levels were independently negatively correlated with leptin levels.

Emerging evidence underscored the significance of leucine-rich repeat-containing G protein-coupled receptor (LGR) 4 in endocrine and metabolic disorders. Despite this, its role in LGR4 in hepatic glucose metabolism remains poorly understood. In this study we set out to test whether LGR4 regulates glucose production in liver through a specific signaling pathway.

Hepatic glucose production and gluconeogenic gene expressions were detected after silence of LGR4 in three obese mice models. Then, whole-body LGR4-deficient (LGR4 KO) mice, liver-specific LGR4 knockout (LGR4LKO) mice, and liver-specific LGR4 overexpression (LGR4LOV) mice were generated, in which we analyzed the effects of LGR4 on hepatic glucose metabolism upon HFD feeding, among which live imaging and quantitative analysis of hepatic phosphoenolpyruvate carboxykinase (PEPCK)-luciferase activity were conducted.

LGR4 expression was significantly upregulated in the liver of three obese mouse models, and presented dynamic expression patterns in response to nutritional fluxes. We utilized global and liver-specific LGR4 knockouts (LGR4LKO), along with adenoviral-mediated LGR4 knockdown in mice, to show improved glucose tolerance and decreased hepatic gluconeogenesis. Specifically, the expression of rate-limiting gluconeogenic enzymes, PEPCK was significantly downregulated. Conversely, mouse model with adenovirus-mediated LGR4 overexpression (LGR4LOV) exhibited elevated gluconeogenesis and PEPCK expression and reversed the suppression observed in LGR4 knockout models. Notably, neither RANKL nor PKA signaling pathways, which were reported to take part in LGR4's function, were involved in the process of LGR4 regulating PEPCK. Instead, TopFlash reporter system and inhibitors application suggested that LGR4's influence on hepatic gluconeogenesis operates through the canonical Wnt/β-catenin/TCF7L2 signaling pathway.

Overall, these findings underscore a novel mechanism by which LGR4 regulates hepatic gluconeogenesis, presenting a potential therapeutic target for diabetes management.

The trapping of pathogenic ligands can potentially be used to prevent signal transduction mediated by catabolic factor expression in osteoarthritis (OA). Although vaspin is known to function as a pathogenic ligand and represents a novel adipokine, little is known about its function and the impact of its nebulization-based administration in OA. Here we provide a report on the function of vaspin in articular chondrocytes and OA model mice. RNA sequencing analysis and ingenuity pathway analysis demonstrated that vaspin upregulation in chondrocytes triggers OA development-related signaling. Vaspin is upregulated in the injured cartilage of patients with OA and DMM (Destabilization of the Medial Meniscus) mice, and its overexpression induces catabolic factor expression in vitro under OA-mimicked conditions. Col2a1-vaspin Tg (Transgenic) animals showed extensive cartilage degradation, whereas vaspin-/- (knockout) mice exhibited decreased OA development. Furthermore, in silico and biochemical analyses showed that vaspin activates the p38 and JNK signaling pathways to regulate AP-1-driven catabolic factor production and cartilage breakdown. Finally, we identified and characterized a vaspin-targeting nanobody, vas nanobody, and showed that intraarticularly injected vas nanobody could effectively block the vaspin-AP-1 axis to treat OA in DMM mice. Together, our results suggest that blockade of the vaspin-AP-1 axis could be an effective therapeutic approach for preventing OA development.

Obesity is a serious health threat, which has affected 16% of adults globally in 2022 and shows a trend toward youthfulness. Leptin, as a regulator of body weight, can suppress appetite and promote energy expenditure, making it potential in obesity treatment. Nevertheless, with the progress of relevant research, it is worth noting that monotherapy with leptin is not an effective strategy since most obese individuals are hyperleptinemic and resistant to leptin, where high levels of leptin fail to exert its weight-loss effects. Therefore, the potential to unlock the weight-loss properties of leptin using pharmacology to improve resistance has provided a new direction for this field. However, most synthetic medicines have retreated from the market due to their undesirable side effects, while natural products are increasingly sought after for drug development due to their minimal side effects. Indeed, natural products are ideal alternatives to oral synthetic agents since a growing body of research has demonstrated their desirable effects on improving leptin resistance through potential therapeutic targets like the JAK2/STAT3 signaling pathway, protein tyrosine phosphatase 1B, the exchange proteins directly activated by cAMP/Ras-related protein 1 signaling pathway, endoplasmic reticulum stress, pro-opiomelanocortin gene, and leptin levels. This review outlines natural products that can improve leptin resistance by inhibiting or activating these targets and evaluates their efficacy in experiments and human clinical trials, offering insights for the development of anti-obesity agents. However, more high-quality clinical research is necessary to validate these findings, as current clinical evidence is constrained by heterogeneity and small sample sizes.

Extensive evidence has demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RAs) can ameliorate obesity. Our previous studies revealed that (Ex-4)2-Fc, a long-acting GLP-1RA we developed, depends on the leptin pathway to treat obesity. However, the mechanisms linking (Ex-4)2-Fc and leptin resistance remain largely unclear. To address this question, we explored the mechanism of GLP-1RAs from the perspective of the gut microbiota, as increasing evidence indicates an important link between the gut microbiota and obesity. This study aimed to explore the potential role of the gut microbiota in the treatment of GLP-1RAs. We found that (Ex-4)2-Fc treatment reshaped obesity-induced gut microbiota disturbances and substantially increased the abundance of Akkermansia muciniphila (Am). In addition, (Ex-4)2-Fc did not respond well in antibiotic-treated (ATB) Obese mice. Subsequent studies have shown that this defect can be overcome by gavage with Am. In addition, we found that Am enhanced (Ex-4)2-Fc therapy by producing the metabolite inosine. Inosine regulates the macrophage adenosine A2A receptor (A2A) pathway to indirectly reduce leptin levels in adipocytes Thus, elucidating the role of metabolites in regulating the leptin pathway will provide new insights into GLP-1RAs therapy and may lead to more effective strategies for guiding the clinical use of antidiabetic agents.

The underlying connections between obesity and non-alcoholic fatty liver disease (NAFLD) are not fully understood. One potential link might be the imbalanced adipokines and hepatokines. We aimed to explore the associations between specific adipokines/hepatokines and NAFLD in Chinese youth and to determine how these biomarkers mediate the obesity-NAFLD relationship.

We analyzed data from the 10-year follow-up visit of the Beijing Children and Adolescents Metabolic Syndrome (BCAMS) study (n = 509; mean age = 20.2 years) for a comprehensive metabolic risk assessment, including liver ultrasound and plasma measurements of adiponectin, leptin, fibroblast growth factor 21 (FGF21), retinol-binding protein 4 (RBP4), and angiopoietin-like protein 8 (ANGPTL8). Longitudinal analysis was performed on a subgroup (n = 307), with complete baseline (mean age = 12.2 years) and follow-up data. Mediation models assessed how obesity at baseline and follow-up influence NAFLD through these biomarkers.

Participants with NAFLD exhibited a high prevalence of central obesity (90.9%). Both cross-sectional and prospective analyses identified increased RBP4, FGF21, leptin, and decreased adiponectin levels as significant predictors of NAFLD. More adipokine/hepatokine abnormalities were linked to higher NAFLD risk. Furthermore, ratios reflecting adipokine/hepatokine imbalances, including leptin/adiponectin, FGF21/adiponectin, and RBP4/adiponectin, demonstrated stepwise changes correlating with NAFLD severity (all p < 0.05). Mediation analysis indicated that these four adipokines/hepatokines accounted for approximately 72.4% of the central obesity-NAFLD relationship and 80.1% in the subgroup analysis using baseline childhood data.

Dysregulated adipokines/hepatokines may explain the onset or progression of obesity-related NAFLD in youths. Higher RBP4, FGF21 and leptin, alongside lower adiponectin, could serve as early biomarkers for NAFLD.

Obesity is a chronic disease that contributes to the development of insulin resistance, type 2 diabetes (T2D), and cardiovascular risk. Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) co-agonism provide an improved therapeutic profile in individuals with T2D and obesity when compared with selective GLP-1R agonism. Although the metabolic benefits of GLP-1R agonism are established, whether GIPR activation impacts weight loss through peripheral mechanisms is yet to be fully defined. Here, we generated a mouse model of GIPR induction exclusively in the adipocyte. We show that GIPR induction in the fat cell protects mice from diet-induced obesity and triggers profound weight loss (∼35%) in an obese setting. Adipose GIPR further increases lipid oxidation, thermogenesis, and energy expenditure. Mechanistically, we demonstrate that GIPR induction activates SERCA-mediated futile calcium cycling in the adipocyte. GIPR activation further triggers a metabolic memory effect, which maintains weight loss after the transgene has been switched off, highlighting a unique aspect in adipocyte biology. Collectively, we present a mechanism of peripheral GIPR action in adipose tissue, which exerts beneficial metabolic effects on body weight and energy balance.

Obese subjects undergoing weight loss often fear the Yoyo dieting effect, which involves regaining or even surpassing their initial weight. To date, our understanding of such long-term obesity and weight cycling effects is still limited and often based on only short-term murine weight gain and loss studies. This study aimed to investigate the long-term impacts of weight cycling on glycemic control and metabolic health, focusing on adipose tissue, liver, and hypothalamus.

Chow-fed mice and mice subjected to prolonged high-fat diet (HFD) consumption for 20 weeks, followed by 24 weeks of dietary interventions to either induce weight gain, weight loss, or weight cycling were monitored for perturbations in feeding efficiency and glucose homeostasis. Post-mortem analyses included qPCR, Western Blotting, biochemical and microscopical assessments for hepatic steatosis and insulin resistance, hypothalamic and adipose tissue inflammation, and circulating lipid, leptin and IL-6 levels.

Weight cycling led to hyperphagia and rapid weight regain, matching the weights of mice continuously on HFD. Despite weight loss, adipose tissue inflammation persisted with elevated pro-inflammatory markers, macrophage infiltration, and impaired Glut4 expression. HFD-induced dysregulation in hypothalamic expression of orexigenic peptides and synaptic plasticity markers persisted also after weight normalization suggesting long-lasting neural alterations. Weight-cycled mice exhibited higher circulating IL-6 and leptin levels, increased hepatic lipid storage, and dysregulated glucose metabolism compared to those with consistent diets, indicating worsened metabolic effects by Yoyo dieting.

In sum, our study highlights significant metabolic risks associated with weight cycling, particularly following prolonged obesity. Persistent adipose tissue inflammation, perturbed neural peptide and plasticity markers and impaired glucose tolerance emphasize the need for effective and sustainable weight loss strategies to mitigate the adverse outcomes of weight regain and improve long-term metabolic health.

Leptin is an adipose tissue-derived hormone that plays a crucial role in body weight, appetite, and behaviour regulation. Leptin controls energy balance as an indicator of adiposity levels and as a modulator of the reward system, which is associated with liking palatable foods. Obesity is characterized by expanded adipose tissue mass and consequently, elevated concentrations of leptin in blood. Leptin's therapeutic potential for most forms of obesity is hampered by leptin resistance and a narrow dose-response window.

This review describes the current knowledge of the brain regions and intracellular pathways through which leptin promotes negative energy balance and restrains neural circuits affecting food reward. We also describe mechanisms that hinder these biological responses in obesity and highlight potential therapeutic interventions.

Additional research is necessary to understand how pathways engaged by leptin in different brain regions are interconnected in the control of energy balance.

Background: Psoriatic patients tend to develop metabolic syndrome (MS). MS accelerates psoriasis, but the exact molecular mechanisms are poorly understood.Objectives: We aim to investigate the impact of leptin on keratinocyte insulin sensitivity and explore its underlying molecular mechanism, which might play a role in the pathogenesis of this disease.Methods: ELISA and immunohistochemistry were applied respectively to detect the level of leptin in serum and in lesion of psoriatic patients with and without MS. The HaCaT cell line was cultured and western-blot assay was performed to assess the change of insulin sensibility. q-PCR and western-blot assay were applied to detect the SOCS3 expressions. Knockdown of SOCS3 were generated in HaCaT cell line by siRNA. Leptin and insulin were treated for 6 days and K10 expression was evaluated by western-blot assay.Results: Patients with MS had higher level of leptin in serum and lesions than their counterparts without MS. Serum levels of leptin was negatively correlated to PASI decline index in psoriatic patients. Long-term treatment of leptin induced insulin resistance in HaCaT cell line, as indicated by elevated expression of p-IRS-1 (ser636) and lower p-PKB (ser473). Leptin treatment up-regulated the mRNA and protein expression of SOCS3. Knockdown of SOCS3 blocked the effect of leptin-induced insulin resistance. Leptin treatment attenuated insulin-elicited K10 expression.Conclusions: Leptin induces insulin resistance by upregulating SOCS3 and give rise to differentiation disorder of keratinocyte. Insulin resistance may serve as a target for anti-psoriatic therapies.

Leptin has been established as the prototype adipose tissue secreted hormone and as a major regulator of several human physiology functions. Here, we are primarily reviewing the findings from studies in humans involving leptin administration. We are describing the metabolic, endocrine and immunologic effects of leptin replacement in conditions of leptin deficiency, such as short-term fasting in healthy individuals, relative energy deficiency in sports (REDS), congenital leptin deficiency (CLD), generalized (GL) and partial lipodystrophy (PL), HIV-associated lipodystrophy (HIV-L) and of leptin treatment in conditions of leptin excess (common obesity, type 2 diabetes, steatotic liver disease). We are comparing the results with the findings from preclinical models and present the main conclusions regarding the role of leptin in human physiology, pathophysiology and therapeutics. We conclude that, in conditions of energy deficiency, leptin substitution effectively reduces body weight and fat mass through reduction of appetite, it improves hypertriglyceridemia, insulin resistance and hepatic steatosis (especially in GL and PL), it restores neuroendocrine function (especially the gonadotropic axis), it regulates adaptive immune system cell populations and it improves bone health. On the contrary, leptin treatment in conditions of leptin excess, such as common obesity and type 2 diabetes, does not improve any metabolic abnormalities. Strategies to overcome leptin tolerance/resistance in obesity and type 2 diabetes have provided promising results in animal studies, which should though be tested in humans in randomized clinical trials.

Addressing abdominal obesity requires multifaceted strategies, with physical activity and diet playing a pivotal role. The objective of this study was to assess alterations in body composition, adipokine concentrations, insulin resistance parameters, and lipid metabolism in males with abdominal obesity following two distinct interventions: exercise alone and exercise combined with a specific diet. The study involved 44 males with abdominal obesity (average age 34.7 ± 5.5 years, waist circumference [WC] 110.3 ± 8.5), randomly assigned to three groups: an experimental group with aerobic-resistance exercise (EG, n = 16), an experimental group with aerobic-resistance exercise combined with a high-protein, low-glycemic index carbohydrate diet (EDG, n = 16), both interventions lasting 6 weeks, and a control group without interventions (CG, n = 12). Body composition (body mass [BM], body fat percentage [BF%], fat-free mass [FFM], android body fat percentage [ANDR]), as well as biochemical blood analyses (asprosin [ASP], leptin [LEP], quantitative insulin sensitivity check index [QUICKI], and total cholesterol [TC]), were conducted at baseline and after 6 weeks of intervention. The impact of interventions on the analyzed variables among groups was assessed using mixed ANOVA tests with post-hoc comparisons. Effect size (ES) was also evaluated using 𝜂p2. Significant reductions in ASP concentration after intervention were observed in both EG (p = 0.04) and EDG (p = 0.01). However, post-hoc tests revealed a decrease in LEP only in the EDG group (p < 0.01). In EDG substantial decreases after 6 weeks of intervention were noted in BM (p < 0.01), BF% (p < 0.01), ANDR (p < 0.01) and TC (p < 0.01). The most notable increase in FFM was observed in the EDG group (p < 0.01). More favourable metabolic outcomes were confirmed in the group combining diet with exercise, where there was a notable reduction in ASP levels by 16% and LEP by 48% after 6 weeks of intervention, compared to the group undergoing exercise alone.

Obesity-induced insulin resistance (IR) can precipitate metabolic disorders such as diabetes. Zeaxanthin, a crucial member of the carotenoid family, has been found to mitigate the damage caused by obesity. However, reports on the effects of zeaxanthin on obesity-induced IR are lacking. Our objective was to examine the metabolic regulatory impacts of zeaxanthin on mice subjected to a high-fat diet (HFD) that triggered IR and to explore their influence on gut microbiota regulation. This study constructed a mouse model of metabolic dysfunction caused by lipid-rich nutritional patterns to investigate physiological and biochemical indices, liver pathway expression, and the intestinal microbiota. The mechanisms by which zeaxanthin improved both IR and glucose metabolic disorders were elucidated. The results demonstrate that zeaxanthin effectively suppressed obesity. The fasting blood glucose, area under curve of oral glucose tolerance test and insulin tolerance test, and homeostatic model assessment-insulin resistance (HOMA-IR) indices in the HFDZEA group decreased by 14.9%, 25.2%, 28.9%, and 29.8%. Additionally, zeaxanthin improved the lipid metabolism and alleviated damage to the liver and pancreas while also activating the PI3K/Akt pathway, regulating hepatic gluconeogenesis and the glycogen metabolism. The number of OTUs in the HFDZEA group increased by 29.04%. Zeaxanthin improved the structure and profile of the gastrointestinal microbiome and enhanced its diversity, increasing probiotics abundance, decreasing pathogen abundance, and thereby ameliorating the dysbiosis of enteric microbial communities in rodents with obesity resulting from excessive fat consumption. The outcomes of our analysis provide a rational basis for advancing zeaxanthin-based nutritional products.

Time-restricted eating (TRE) and low-carbohydrate diet (LCD) can improve multiple cardiometabolic parameters in patients with metabolic syndrome (MetS), but their effects on psychosocial health and satiety are unclear. In this study, we aimed to evaluate the effects of TRE, LCD, and their combination (TRE + LCD) on quality of life (QoL), sleep, mood, appetite, and metabolic hormones in patients with MetS.

This is a secondary analysis of a single-center, 3-month, open-label, randomized clinical trial investigating the effects of TRE, LCD, and TRE + LCD on weight and cardiometabolic parameters in individuals with MetS. This secondary analysis examined QoL, sleep, mood, and appetite using the Rand 36-Item Short Form (SF-36); Pittsburgh Sleep Quality Index (PSQI); Depression, Anxiety, and Stress Scale; and Eating Behavior Rating Scale, respectively, as well as measured levels of metabolic hormones including leptin, amylin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 (GLP-1), pancreatic polypeptide (PP), and peptide YY. Between-group comparisons were conducted via one-way ANOVAs and post hoc LSD tests for normally distributed variables or Kruskal‒Wallis H tests and the Nemenyi test for abnormally distributed variables. P < 0.017 was considered significant in multiple comparisons following Bonferroni adjustment.

A total of 162 participants (mean [SD] age, 41.2 [9.9] years; mean [SD] body mass index, 29.3 [3.4] kg/m2; 102 [63%] men) who started the intervention were analyzed. After 3 months, only the TRE group decreased GLP-1 levels (-0.9 [IQR, -1.9 to -0.3] pg/mL; P = 0.002), increased PP levels (8.9 [IQR, -7.6 to 71.8] pg/mL; P = 0.011), physical functioning in the SF-36 (5.2 [95% CI, 1.9 to 8.5]; P = 0.001), social functioning in the SF-36 (9.1 [95% CI, 2.5 to 15.6]; P = 0.005), role-physical in the SF-36 (24.1 [95% CI, 11.8 to 36.4]; P < 0.001), role-emotional in the SF-36 (22.4 [95% CI, 12.6 to 32.2]; P < 0.001), and sleep efficiency in the PSQI (0.29 [95% CI, 0.03 to 0.55]; P = 0.021). Compared with changes in LCD, TRE further increased general health in the SF-36 (9.7 [95% CI, 3.3 to 16.0]; P = 0.006). Relative to the changes of TRE + LCD, TRE significantly increased role-emotional in the SF-36 (19.9 [95% CI 4.9 to 34.8]; P = 0.006). Changes in sleep quality, mood status, appetite, and metabolic hormones did not differ among three groups. Greater weight loss was associated with decreased leptin levels (r = 0.538), decreased amylin levels (r = 0.294), reduced total appetite scores (r = 0.220), and improved general health (r = -0.253) (all P ≤ 0.01).

TRE, LCD, and TRE + LCD all could improve psychosocial health and reduce appetite. Notably, TRE yielded greater benefits in QoL compared with LCD or TRE + LCD in individuals with MetS.

ClinicalTrials.gov Identifier: NCT04475822.

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone secreted by K cells in the small intestine and is considered an obesity-promoting factor. In this study, we systematically investigated the anti-obesity effects of intragastric safflower yellow (SY)/hydroxysafflor yellow A (HSYA) and the underlying mechanism for the first time. Our results showed that intragastric SY/HSYA, rather than an intraperitoneal injection, notably decreased serum GIP levels and GIP staining in the small intestine in diet-induced obese (DIO) mice. Moreover, intragastric SY/HSYA was also first found to significantly suppress GIP receptor (GIPR) signaling in both the hypothalamus and subcutaneous White adipose tissue. Our study is the first to show that intragastric SY/HSYA obviously reduced food intake and body weight gain in leptin sensitivity experiments and decreased serum leptin levels in DIO mice. Further experiments demonstrated that SY treatment also significantly reduced leptin levels, whereas the inhibitory effect of SY on leptin levels was reversed by activating GIPR in 3 T3-L1 adipocytes. In addition, intragastric SY/HSYA had already significantly reduced serum GIP levels and GIPR expression before the serum leptin levels were notably changed in high-fat-diet-fed mice. These findings suggested that intragastric SY/HSYA may alleviate diet-induced obesity in mice by ameliorating hyperleptinemia via dual inhibition of the GIP-GIPR axis.

To evaluate the effects of intermittent hypoxia-reoxygenation (IHR) on body weight, diet and water intake, circulating metabolites, and responses to central leptin injection in a rat model of diet-induced obesity (DIO).

Rat models of DIO established by 12-week high-fat diet (HFD) feeding were randomized into normoxia group (n=15), intermittent hypoxia group (6% O2, 30 cycles/h, 8 h/day for 4 weeks; n=15), and IHR group (2 weeks of intermittent hypoxia followed by 2 weeks of reoxygenation; n=15). Body weight, diet and water intake of the rats were recorded, and circulating leptin, IL-6, and Ang-II levels were detected. After IHR treatment, the rats received intracerebroventricular injection of 4 μg leptin, and the hypothalamus and liver were taken 1 h later for detecting POMC, FRA-1 and FRA-2 expressions in the hypothalamus using immunohistochemistry, POMC, pSTAT3 and LepR expressions in the hypothalamus using Western blotting, and LepR mRNA expression in the hypothalamus and liver using RT-PCR.

The rats in intermittent hypoxia group showed significantly increased weight gain, food intake and elevated systemic inflammatory cytokine levels. Intermittent hypoxia obviously inhibited the expression of POMC, lowered the expressions of FRA-1 and pSTAT3, reduced the responsiveness of the rats to exogenous leptin, and downregulated the mRNA and protein expression of LepR. Two weeks of reoxygenation treatment obviously reduced intermittent hypoxia-induced weight gain and metabolic disorder and improved leptin sensitivity of the rats.

Prolonged intermittent hypoxia impairs hypothalamic leptin signaling by downregulating LepR expression to promote weight gain in obese rats, which can be improved by reoxygenation treatment.

Fibro-calcific aortic valve disease (FCAVD) is a progressive disorder characterized by the thickening and calcification of the aortic valve, eventually leading to aortic stenosis. Adiponectin and leptin, known for their anti-inflammatory and proinflammatory properties, respectively, have been implicated in cardiovascular diseases, but their associations with FCAVD are controversial. This meta-analysis aims to evaluate the relationships between adiponectin and leptin levels and FCAVD, particularly in patients with severe aortic stenosis (AS).

A systematic search was conducted across the PubMed, Scopus, and Web of Science databases to identify studies on adiponectin and leptin levels in FCAVD. The methodological quality of each study was assessed using the Newcastle-Ottawa Scale. Standardized mean differences (SMDs) and 95% confidence intervals (CIs) were calculated, and publication bias was evaluated using Egger's test and funnel plots.

Out of 191 articles identified, 10 studies involving 2360 patients (989 with FCAVD and 1371 controls) were included. The analysis suggested trends in the associations of lower adiponectin levels (SMD = -0.143, 95% CI: -0.344, 0.057, p = 0.161) and higher leptin levels (SMD = 0.175, 95% CI: -0.045, 0.395, p = 0.119) with FCAVD. The association remained a trend for low adiponectin but showed a significant correlation with high leptin in severe AS patients (SMD = 0.29, 95% CI: 0.036, 0.543, p = 0.025).

This meta-analysis indicates a potential association between elevated leptin levels and severe aortic stenosis, while the relationship with adiponectin levels remains inconclusive. These findings highlight the need for further and dedicated research to clarify the roles of these adipokines in the pathogenesis of FCAVD and their potential roles as biomarkers for disease progression.

Gestational diabetes mellitus (GDM) presents varied manifestations throughout pregnancy and poses a complex clinical challenge. High-depth cell-free DNA (cfDNA) sequencing analysis holds promise in advancing our understanding of GDM pathogenesis and prediction. In 299 women with GDM and 299 matched healthy pregnant women, distinct cfDNA fragment characteristics associated with GDM are identified throughout pregnancy. Integrating cfDNA profiles with lipidomic and single-cell transcriptomic data elucidates functional changes linked to altered lipid metabolism processes in GDM. Transcription start site (TSS) scores in 50 feature genes are used as the cfDNA signature to distinguish GDM cases from controls effectively. Notably, differential coverage of the islet acinar marker gene PRSS1 emerges as a valuable biomarker for GDM. A specialized neural network model is developed, predicting GDM occurrence and validated across two independent cohorts. This research underscores the high-depth cfDNA early prediction and characterization of GDM, offering insights into its molecular underpinnings and potential clinical applications.

Coordinated detection of changes in metabolic state by the nervous system is fundamental for survival. Hypothalamic pro-opiomelanocortin (POMC) neurons play a critical role in integrating metabolic signals, including leptin levels. They also coordinate adaptative responses and thus represent an important relay in the regulation of energy balance. Despite a plethora of work documenting the effects of individual hormones, nutrients, and neuropeptides on POMC neurons, the importance for crosstalk and additive effects between such signaling molecules is still underexplored. The ability of the metabolic state and the concentrations of nutrients, such as glucose, to influence leptin's effects on POMC neurons appears critical for understanding the function and complexity of this regulatory network. Here, we summarize the current knowledge on the effects of leptin on POMC neuron electrical excitability and discuss factors potentially contributing to variability in these effects, with a particular focus on the mouse models that have been developed and the importance of extracellular glucose levels. This review highlights the importance of the metabolic "environment" for determining hypothalamic neuronal responsiveness to metabolic cues and for determining the fundamental effects of leptin on the activity of hypothalamic POMC neurons.

A wealth of evidence underscores the bioactive properties of nutraceuticals and functional foods in addressing oxyinflammatory-based diseases with implications at both peripheral and central levels. Opuntia ficus-indica (OFI) is well-documented for its health-promoting attributes, though its fruit (OFIF) remains relatively understudied. Not only poses Metabolic Syndrome (MetS) cardiometabolic risks but also contributes significantly to cognitive impairment, especially in crucial brain areas such as hippocampus and hypothalamus.

Following 8 weeks of HFD to induce MetS, rats received OFIF oral supplementation for 4 weeks to evaluate cognitive and affective modifications using behavioural paradigms, i.e. open field, burrowing, white-dark box, novelty-suppressed feeding, and object recognition tests. Our investigation extended to biochemical evaluations of lipid homeostasis, central and peripheral oxidative stress and neurotrophic pathways, correlating these measures together with circulating leptin levels.

Our data revealed that OFIF modulation of leptin positively correlates with systemic and brain oxidative stress, with markers of increased anxiety-like behaviour and impaired lipid homeostasis. On the other hand, leptin levels reduced by OFIF are associated with improved antioxidant barriers, declarative memory and neurotrophic signalling.

This study underscores OFIF neuroactive potential in the context of MetS-associated cognitive impairment, offering insights into its mechanisms and implications for future therapeutic strategies.

Many microRNAs (miRNAs) have been identified as being involved in diabetes; however, the question of which ones may be the most promising therapeutical targets still needs more investigation. This study aims to understand the overall development tendency and identify a specific miRNA molecule to attenuate diabetes. We developed a combined analysis method based on bibliometrics and bioinformatics to visualize research institutions, authors, cited references, and keywords to identify a promising target for diabetes. Our data showed that diabetes-related miRNA is receiving continuously increasing attention, with a large number of publications, indicating that this is still a hot topic in diabetes research. Scientists from different institutions are collaborating closely in this field. miR-21, miR-146a, miR-155, and miR-34a are frequently mentioned as high-frequency keywords in the related references. Moreover, among all the above miRNAs, bioinformatics analysis further strengthens the argument that miR-21 is the top significantly upregulated molecule in diabetes patients and plays an important role in the pathogenesis of diabetes. Our study may provide a way to identify targets and promote the clinical translation of miRNA-related therapeutical strategies for diabetes, which could also indicate present and future directions for research in this area.

Exercise training is a valuable tool for improving body weight and composition in overweight or obese adults, which leads to a negative energy balance. It is relevant to consider whether exercise can help people lose weight or prevent weight gain because any energy expended in exercise increases the severity of hunger and promotes food consumption. Over the past decade, the identification of the circulating peptide ghrelin, which alerts the brain to the body's nutritional state, has significantly expanded our understanding of this homeostatic mechanism that controls appetite and body weight. To shed more light on this issue, we decided to investigate the effects of resistance and endurance training on plasma ghrelin and leptin levels. In addition, we sought to understand the mechanisms by which acute and chronic exercise can regulate hunger. This review analyzes studies published in the last fifteen years that focused on changes suffered by ghrelin, leptin, or both after physical exercise in overweight or obese individuals. Most studies have shown a decrease in leptin levels and an increase in ghrelin levels in these cases. Exercise regimens that support weight maintenance need further investigation.

Co-treatment with long acting PYY and the GLP-1 receptor agonists has potential as an efficient obesity treatment. This study investigates whether the mechanisms behind additive reduction of food intake and weight loss depends on complementary effects in brain areas regulating food intake and if restoration of leptin sensitivity is involved.

Diet-induced obese (DIO) mice were co-treated with PYY(3-36) and exendin-4 (Ex4, GLP-1R agonist) for 14 days using minipumps. Leptin responsiveness was evaluated by measuring food intake and body weight after leptin injection, and gene expression profile was investigated in various of brain regions and liver.

We show that weight loss associated with co-treatment of PYY(3-36) and Ex4 and Ex4 mono-treatment in DIO mice increased expression of several genes in area postrema (AP) known to be involved in appetite regulation and Cart, Pdyn, Bdnf and Klb were synergistically upregulated by the co-treatment. The upregulations were independent of weight loss, as shown by inclusion of a weight matched control. Moreover, PYY(3-36) and Ex4 co-treatment resulted in synergistically upregulated plasma concentrations of soluble leptin receptor (SLR) and improved sensitivity to exogenous leptin demonstrated by food intake lowering.

The study results suggest that synergistic upregulation of appetite-regulating genes in AP and improved leptin sensitivity are important mediators for the additive weight loss resulting from PYY and Ex4 co-treatment.

Although significant advances have been made in understanding the patho-physiology of psychiatric disorders (PDs), therapeutic advances have not been very convincing. While psychotropic medications can reduce classical symptoms in patients with PDs, their long-term use has been reported to induce or exaggerate various pre-existing metabolic abnormalities including diabetes, obesity and non-alcoholic fatty liver disease (NAFLD). The mechanism(s) underlying these metabolic abnormalities is not clear; however, lipid/fatty acid accumulation due to enhanced de novo lipogenesis (DNL) has been shown to reduce membrane fluidity, increase oxidative stress and inflammation leading to the development of the aforementioned metabolic abnormalities. Intriguingly, emerging evidence suggest that DNL dysregulation and fatty acid accumulation could be the major mechanisms associated with the development of obesity, diabetes and NAFLD after long-term treatment with psychotropic medications in patients with PDs. In support of this, several adjunctive drugs comprising of anti-oxidants and anti-inflammatory agents, that are used in treating PDs in combination with psychotropic medications, have been shown to reduce insulin resistance and development of NAFLD. In conclusion, the above evidence suggests that DNL could be a potential pathological factor associated with various metabolic abnormalities, and a new avenue for translational research and therapeutic drug designing in PDs.

Leptin regulates lipid metabolism, maximizing insulin sensitivity; however, peripheral leptin resistance is not fully understood, and its contribution to metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. This study evaluated the contribution of the leptin axis to MASLD in humans. Forty-three participants, mostly female (86.04%), who underwent cholecystectomy were biopsied. Of the participants, 24 were healthy controls, 8 had MASLD, and 11 had metabolic dysfunction-associated steatohepatitis (MASH). Clinical and biochemical data and the gene expression of leptin, leptin receptor (LEPR), suppressor of cytokine signaling 3 (SOCS3), sterol regulatory element-binding transcription factor 1 (SREBF1), stearoyl-CoA desaturase-1 (SCD1), and patatin-like phospholipase domain-containing protein 2 (PNPLA2), were determined from liver and adipose tissue. Higher serum leptin and LEPR levels in the omental adipose tissue (OAT) and liver with MASH were found. In the liver, LEPR was positively correlated with leptin expression in adipose tissue, and SOCS3 was correlated with SREBF1-SCD1. In OAT, SOCS3 was correlated with insulin resistance and transaminase enzymes (p < 0.05 for all. In conclusion, we evidenced the correlation between the peripheral leptin resistance axis in OAT-liver crosstalk and the complications of MASLD in humans.

Nutritional, endocrine, and neurological signals converge in multiple brain centres to control feeding behaviour and food intake as part of the allostatic regulation of energy balance. Among the several neuroendocrine systems involved, the leptin, glucocorticoid, and glucagon-like peptide 1 (GLP1) systems have been extensively researched. Leptin is at the top hierarchical level since its complete absence is sufficient to trigger severe hyperphagia. Glucocorticoids are key regulators of the energy balance adaptation to stress and their sustained excess leads to excessive adiposity and metabolic perturbations. GLP1 participates in metabolic adaptation to food intake, regulating insulin secretion and satiety by parallel central and peripheral signalling systems. Herein, we review the brain and peripheral targets of these three hormone systems that integrate to regulate food intake, feeding behaviour, and metabolic homeostasis. We examine the functional relationships between leptin, glucocorticoids, and GLP1 at the central and peripheral levels, including the cross-regulation of their circulating levels and their cooperative or antagonistic actions at different brain centres. The pathophysiological roles of these neuroendocrine systems in dysregulated intake are explored in the two extremes of body adiposity - obesity and lipodystrophy - and eating behaviour disorders.

The current obesity pandemic has given rise to associated comorbidities and complications, including type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). During the last decade, certain glucagon-like peptide 1 receptor agonists (GLP-1RA), originally developed as antihyperglycemic drugs, also demonstrated efficacy for weight loss.

To review shared pathophysiologic features of common metabolic diseases and compare therapeutic strategies to reduce body weight and related complications.

We performed an extensive literature research to describe the effects of lifestyle modification, first-generation anti-obesity drugs, and GLP-1RA on weight loss in humans with obesity, type 2 diabetes and MASLD.

Until recently, treatment of obesity has been limited to lifestyle modification, which offer moderate degree and sustainability of weight loss. The few approved first-generation anti-obesity drugs are either limited to short term use or to certain forms of obesity. Some GLP-1RA significantly decrease caloric intake and body weight. Liraglutide and semaglutide have therefore been approved for treating people with obesity. They also lead to a reduction of hepatic fat content and inflammation in people with biopsy-confirmed MASLD. Possible limitations comprise adverse effects, treatment adherence and persistence.

Certain GLP-1RA are superior to lifestyle modification and first-generation anti-obesity drugs in inducing weight loss. They have therefore markedly changed the portfolio of obesity treatment with additional beneficial effects on steatotic liver disease.

Although obesity is a recognized risk factor of atrial fibrillation (AF), the mechanisms are not fully understood.

We aimed to identify the potential mediators between body mass index (BMI) and AF.

We conducted a two-sample Mendelian randomization (MR) analysis using publicly available summary-level data from genome-wide association studies. Univariable MR analyses were applied to identify potential mediators, and then the multivariable MR analyses were conducted to explore the mediated roles of circulating biomarkers, metabolic markers and comorbidities in the association between BMI and AF.

This MR study found a significant causal association between BMI and AF (OR = 1.41, 95% CI = 1.33-1.50; p < 0.001), which was attenuated to 1.21 (95% CI = 1.03-1.43) after being adjusted for leptin, in which 48.78% excess risk was mediated. After further adjustment for leptin and some cormorbidies, the association was attenuated to null (adjusted for leptin and sleep apnoea: OR=1.05, 95% CI = 0.85-1.30; adjusted for leptin and coronary heart disease: OR = 1.08, 95% CI = 0.90-1.30; adjusted for leptin and systolic blood pressure: OR = 1.11, 95% CI = 0.88-1.41), resulting in 87.80%, 80.49% and 73.17% excess risk being mediated, respectively.

These results identified an important mediated role of leptin, particularly for individuals with sleep apnoea, coronary heart disease or hypertension, providing some clues for the underlying mechanisms behind the impact of obesity on AF risk.

Obesity is the modern world's current epidemic, with substantial health and economic impact. This study aimed to provide a narrative overview of the past, currently available, and future treatment options that offer therapeutic and preventive advantages for obesity management.

Historically, rimonabant, and lorcaserin, were approved and used for managing non-syndromic obesity. Currently, orlistat, naltrexone/bupropion, glucagon-like peptide-1 receptor agonist (GLP-1 RA), and a few promising therapeutic agents are under investigation, including retatrutide, cagrilintide and orforglipron, which show promising weight reduction effects. We have developed a search string of the Medical Subject Headings (MeSH), including the terms GLP-1 RAs, obesity, and weight loss. This string was then used to perform a systematic literature search in the database including PubMed, EMBASE, MEDLINE, and Scopus up to January 31st, 2024.

Managing obesity often requires medical interventions, particularly in cases of severe obesity or obesity-related comorbidities. Thus, it is important to approach obesity management holistically, considering individual needs and circumstances. In our opinion, consulting with healthcare professionals is crucial to developing a personalized plan that addresses both weight loss and overall health improvement.

In addition to their pivotal roles in energy storage and expenditure, adipose tissues play a crucial part in the secretion of bioactive molecules, including peptides, lipids, metabolites, and extracellular vesicles, in response to physiological stimulation and metabolic stress. These secretory factors, through autocrine and paracrine mechanisms, regulate various processes within adipose tissues. These processes include adipogenesis, glucose and lipid metabolism, inflammation, and adaptive thermogenesis, all of which are essential for the maintenance of the balance and functionality of the adipose tissue micro-environment. A subset of these adipose-derived secretory factors can enter the circulation and target the distant tissues to regulate appetite, cognitive function, energy expenditure, insulin secretion and sensitivity, gluconeogenesis, cardiovascular remodeling, and exercise capacity. In this review, we highlight the role of adipose-derived secretory factors and their signaling pathways in modulating metabolic homeostasis. Furthermore, we delve into the alterations in both the content and secretion processes of these factors under various physiological and pathological conditions, shedding light on potential pharmacological treatment strategies for related diseases.

The exponential increase in diabetes mellitus (DM) poses serious public health concerns. In this review, we focus on the role of leptin in type 2 DM. The peripheral actions of leptin consist of upregulating proinflammatory cytokines which play an important role in the pathogenesis of type 2 DM and insulin resistance. Moreover, leptin is known to inhibit insulin secretion and plays a significant role in insulin resistance in obesity and type 2 DM. A literature search was conducted on Medline, Cochrane, Embase, and Google Scholar for relevant articles published until December 2023. The following search strings and Medical Subject Headings (MeSH terms) were used: "Diabetes Mellitus," "Leptin," "NPY," and "Biomarker." This article aims to discuss the physiology of leptin in type 2 DM, its glucoregulatory actions, its relationship with appetite, the impact that various lifestyle modifications can have on leptin levels, and, finally, explore leptin as a potential target for various treatment strategies.

Ten-eleven translocation (TET) 2 is an enzyme that catalyzes DNA demethylation to regulate gene expression by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, functioning as an essential epigenetic regulator in various biological processes. However, the regulation and function of TET2 in adipocytes during obesity are poorly understood. In this study, we demonstrate that leptin, a key adipokine in mammalian energy homeostasis regulation, suppresses adipocyte TET2 levels via JAK2-STAT3 signaling. Adipocyte Tet2 deficiency protects against high-fat diet-induced weight gain by reducing leptin levels and further improving leptin sensitivity in obese male mice. By interacting with C/EBPα, adipocyte TET2 increases the hydroxymethylcytosine levels of the leptin gene promoter, thereby promoting leptin gene expression. A decrease in adipose TET2 is associated with obesity-related hyperleptinemia in humans. Inhibition of TET2 suppresses the production of leptin in mature human adipocytes. Our findings support the existence of a negative feedback loop between TET2 and leptin in adipocytes and reveal a compensatory mechanism for the body to counteract the metabolic dysfunction caused by obesity.

Obesity is epidemic and of great concern because of its comorbid and costly inflammatory-driven complications. Extensive investigations in mice have elucidated highly coordinated, well-balanced interactions between adipocytes and immune cells in adipose tissue that maintain normal systemic metabolism in the lean state, while in obesity, proinflammatory changes occur in nearly all adipose tissue immune cells. Many of these changes are instigated by adipocytes. However, less is known about obesity-induced adipose-tissue immune cell alterations in humans. Upon high-fat diet feeding, the adipocyte changes its well-known function as a metabolic cell to assume the role of an immune cell, orchestrating proinflammatory changes that escalate inflammation and progress during obesity. This transformation is particularly prominent in humans. In this review, we (a) highlight a leading and early role for adipocytes in promulgating inflammation, (b) discuss immune cell changes and the time course of these changes (comparing humans and mice when possible), and (c) note how reversing proinflammatory changes in most types of immune cells, including adipocytes, rescues adipose tissue from inflammation and obese mice from insulin resistance.

Partial leptin reduction can induce significant weight loss, while weight loss contributes to partial leptin reduction. The cause-and-effect relationship between leptin reduction and weight loss remains to be further elucidated. Here, we show that FGF21 and the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide rapidly induced a reduction in leptin. This leptin reduction contributed to the beneficial effects of GLP-1R agonism in metabolic health, as transgenically maintaining leptin levels during treatment partially curtailed the beneficial effects seen with these agonists. Moreover, a higher degree of leptin reduction during treatment, induced by including a leptin neutralizing antibody with either FGF21 or liraglutide, synergistically induced greater weight loss and better glucose tolerance in diet-induced obese mice. Furthermore, upon cessation of either liraglutide or FGF21 treatment, the expected immediate weight regain was observed, associated with a rapid increase in circulating leptin levels. Prevention of this leptin surge with leptin neutralizing antibodies slowed down weight gain and preserved better glucose tolerance. Mechanistically, a significant reduction in leptin induced a higher degree of leptin sensitivity in hypothalamic neurons. Our observations support a model that postulates that a reduction of leptin levels is a necessary prerequisite for substantial weight loss, and partial leptin reduction is a viable strategy to treat obesity and its associated insulin resistance.