Leptin, a key adipokine regulating energy homeostasis, has been extensively studied for its potential in the management of obesity. However, its therapeutic efficacy is often limited due to leptin resistance. This review synthesizes animal and clinical evidence on leptin’s role in obesity, focusing on models such as genetically deficient mice (e.g., ob/ob, db/db), diet-induced obesity mice, and clinical conditions such as congenital leptin deficiency (CLD), leptin receptor deficiency (LRD), lipodystrophy, and common obesity. The mechanisms underlying leptin resistance are summarized, including hyperleptinemia, impaired JAK2–STAT3 signaling, reduced blood–brain barrier permeability, defective autophagy, endoplasmic reticulum stress, inflammation, decreased leptin receptor expression, leptin signaling pathway dysfunction, increased mTOR activity, and peripheral leptin resistance. Due to these leptin receptor and/or post-receptor signaling pathway defects, leptin or its analogs usually fail to produce the expected weight-loss effect in individuals with overweight or obesity, although they remain highly effective in individuals with CLD and lipodystrophy, as well as in ob/ob mice. Alternative strategies, such as melanocortin-4 receptor (MC4R) agonists (e.g., setmelanotide) for LRD treatment, are very promising. Future directions include enhancing leptin sensitization, combining leptin with other drugs, and exploring partial leptin reduction to mitigate compensatory responses during weight loss. The review emphasizes the complexity of leptin resistance and the necessity of targeted approaches in obesity therapy.

Nuciferine (Nuci), the main aporphine alkaloid component in lotus leaf, was reported to reduce lipid accumulation in vitro. Herein we investigated whether Nuci prevents obesity in high fat diet (HFD)-fed mice and the underlying mechanism in liver/HepG2 hepatocytes and epididymal white adipose tissue (eWAT) /adipocytes. Male C57BL/6J mice were fed with HFD supplemented with Nuci (0.10%) for 12 weeks. We found that Nuci significantly reduced body weight and fat mass, improved glycolipid profiles, and enhanced energy expenditure in HFD-fed mice. Nuci also ameliorated hepatic steatosis and decreased the size of adipocytes. Furthermore, Nuci remarkably promoted the phosphorylation of AMPK, suppressed lipogenesis (SREBP1, FAS, ACC), promoted lipolysis (HSL, ATGL), and increased the expressions of adipokines (FGF21, ZAG) in liver and eWAT. Besides, fatty acid oxidation in liver and thermogenesis in eWAT were also activated by Nuci. Similar results were further observed at cellular level, and these beneficial effects of Nuci in cells were abolished by an effective AMPK inhibitor compound C. In conclusion, Nuci supplementation prevented HFD-induced obesity, attenuated hepatic steatosis, and reduced lipid accumulation in liver/hepatocytes and eWAT/adipocytes through regulating AMPK-mediated FAS/HSL pathway. Our findings provide novel insight into the clinical application of Nuci in treating obesity and related complications.

Objectives Lotus leaf is a kind of traditional Chinese medicine. We aimed to explore the effects of lotus leaf aqueous extract (LLAE) on peroxisome proliferative activated receptor γ2 (PPARγ2) expression in preadipocytes and adipocytes and further investigate its effects on high fat diet (HFD)-induced obese rats. Methods pGL3-Enhancer-PPARγ2 (625bp)-Luc plasmid, a luciferase reporter gene expression plasmid containing PPARγ2 promoter, was stably transfected into 3T3-L1 preadipocytes. PPARγ2 promoter activities were determined by assaying the luciferase activities. Then PPARγ2 promoter activities in preadipocytes and PPARγ2 mRNA levels in human subcutaneous adipocytes were measured after the administration with LLAE. Additionally, the effects of LLAE on body weight, fat mass, glucose and lipid metabolism and the expression of PPARγ2, insulin receptor substrate 1 (IRS1) and glucose transporter 4 (GLUT4) in visceral adipose tissue (VAT) were measured in HFD-induced obese rats treated with low or high dose [0.5 g or 3.0 g crude drug / (kg.d)] LLAE for six weeks. Results 10 μg/ml LLAE significantly increased the luciferase activities in 3T3-L1 cells and the stimulatory action reached 2.51 folds of controls when LLAE was 1000 μg/ml (P<0.01). After treating 3T3-L1 cells with 100 μg/ml LLAE, the stimulatory role peaked at 32 h where it was 2.58 folds of controls (P<0.01). Besides, 100 μg/ml LLAE significantly increased PPARγ2 mRNA levels in human adipocytes to 1.91 folds of controls (P<0.01). In HFD-induced obese rats, administration with both low and high dose LLAE notably reduced visceral fat mass by 45.5 % and 58.4 %, respectively, and significantly decreased fasting serum insulin levels (P<0.05). The high dose LLAE also significantly decreased homeostasis model assessment of insulin resistance (HOMA-IR) in obese rats (P<0.05). Furthermore, the mRNA levels of PPARγ2 and GLUT4 in VAT of obese rats were significantly increased when compared with control rats, and were notably suppressed by LLAE intervention for six weeks (P<0.05). Conclusions LLAE significantly reduces visceral fat mass and ameliorates insulin resistance in HFD-induced obese rats. These beneficial effects of LLAE may associate with its role in stimulating PPARγ2 expression in preadipocytes and subcutaneous adipocytes and suppressing PPARγ2 and GLUT4 expression in VAT.

Objectives: To explore the activating transcription factor 3 (ATF3) and fibronectin type III domain-containing protein 5 (FNDC5)/irisin protein levels in serum and mRNA levels in subcutaneous and visceral white adipose tissue (sWAT and vWAT) in normal-weight (NW) and overweight/obese (OW/OB) patients with colorectal cancer (CRC). Methods: 76 CRC patients and 40 healthy controls were recruited. Serum ATF3 and irisin levels were detected by using ELISA kits, and the mRNA expression levels in sWAT and vWAT were measured by performing RT-qPCR. Results: The serum ATF3 levels were greater by 37.2%, whereas the irisin levels were lower by 23.3% in NW+CRC patients compared with those in healthy controls. CRC was independently associated with both ATF3 and irisin levels. The probability of CRC greater by 22.3-fold in individuals with high ATF3 levels compared with those with low ATF3 levels, whereas the risk of CRC in subjects with high irisin levels was lower by 78.0% compared to the risk in those with low irisin levels after adjustment for age, gender, BMI, and other biochemical parameters. Serum ATF3 and irisin could differentiate CRC patients from controls with receiver operating characteristic (ROC) curve areas of 0.745 (95% CI, 0.655–0.823) and 0.656 (95% CI, 0.561–0.743), respectively. The combination of ATF3 and irisin exhibited improved diagnosis value accuracy with ROC curve areas of 0.796 (95% CI, 0.710–0.866) as well as 72.6% sensitivity and 80.0% specificity. Conclusion: Increased ATF3 and reduced irisin levels were observed in sera from CRC patients. Individuals with high ATF3 and low irisin levels were more likely to have CRC. ATF3 and irisin represent potential diagnostic biomarkers for CRC patients.

Zinc-α2-glycoprotein (ZAG) plays an important role in the regulation of body weight, body fat, and glucose metabolism. In this study, we first measured ZAG levels in serum and ZAG mRNA levels in subcutaneous white adipose tissue (sWAT) among overweight/obese patients and lean control subjects. Second, we investigated the effects of ZAG administration on the body weight, body fat and glucose metabolism of high-fat diet (HFD)-induced obese ICR mice and the possible mechanisms involved. The results showed that serum ZAG and mRNA levels in sWAT were significantly decreased in overweight/obese patients and that both showed a negative association with body mass index (BMI) and body weight after adjustment for age and sex. Further partial correlation analysis found that ZAG mRNA expression was positively related with several WAT browning-related genes, including uncoupling protein 1 (UCP1) (r = 0.67) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1a) (r = 0.60), in the sWAT of all subjects. Additionally, intraperitoneal injection of a ZAG expression plasmid (5 μg/injection, four times a week) in HFD-induced obese mice for 8 weeks demonstrated that ZAG overexpression significantly decreased body weight and WAT mass, and greatly increased the glucose tolerance of obese mice, as shown by the intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test (IPITT). The staining of UCP1-positive adipocytes was significantly stronger in the sWAT of ZAG-treated obese mice than in that of obese control mice. The mRNA and protein levels of PGC1α in sWAT were significantly increased to 2.2- and 5.3-fold, respectively, compared with HFD obese mice, and there was a strong positive correlation between the expression levels of Zag and Pgc1α in mouse sWAT (r = 0.74). A similar phenomenon was also observed in visceral white adipose tissue (vWAT): the mRNA and protein levels of PGC1α were increased to 1.9- and 3.6-fold, respectively, when obese mice were treated with ZAG. In conclusion, ZAG levels in both sWAT and serum are inversely related with BMI and body weight in Chinese subjects. The action of ZAG on body weight, fat mass and glucose metabolism may be realized through activating PGC1α expression in sWAT and vWAT, then promoting WAT browning in obese mice.

Objective: Adipose tissue insulin resistance is a common feature of obesity-related metabolic diseases. However, the relationship between adipose tissue insulin resistance and metabolic syndrome (MS) has not been fully elucidated. Here, we explored the relationship between the adipose tissue insulin resistance index (Adipo-IR) (fasting insulin × free fatty acids) and MS and the predictive power of Adipo-IR for MS in northern Chinese populations. Methods: A total of 312 subjects, 186 subjects with MS, 80 nonmetabolic syndrome (NMS) subjects with central obesity, and 46 normal controls were recruited. The general clinical information, biochemical measurements, and oral glucose tolerance tests were evaluated. Serum adiponectin levels were determined using enzyme linked immunosorbent assay (ELISA). Results: Adipo-IR was 2.32-fold higher in NMS subjects and 2.62-fold higher in MS subjects than in normal controls in male subjects; in female subjects, it was 1.75-fold and 3.58-fold higher, respectively (P < 0.05). Female subjects with MS had higher Adipo-IR than male subjects (P < 0.001). Adipo-IR was independently positively correlated with waist circumference, triglyceride, aspartate aminotransferase, and fasting blood glucose and negatively correlated with adiponectin (P < 0.05). Subjects with the highest Adipo-IR tertile had a 2.758-fold higher risk of MS than subjects with the lowest tertile after adjusting for potential confounders (95% confidence interval: 1.552– 9.096; P = 0.003). Receiver operating characteristic curve analysis showed that the predictive power of Adipo-IR for MS was 73.1% and 79.2% in male and female subjects, respectively, with optimal cutoff values of 3.84 and 5.92 mU/L×mmol/L. Conclusion: Adipo-IR provides a simple method to study adipose tissue insulin sensitivity. Adipo-IR is associated with MS and is an important predictor of MS.