Leptin Sensitivity Research Articles

Low-dose valine attenuates diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) in mice by enhancing leptin sensitivity and modulating the gut microbiome

Elevated circulating branched-chain amino acids (BCAAs) have been associated with obesity, insulin resistance, and MASLD, yet BCAA supplementation has been shown to provide protective outcomes towards the intervention of MASLD. Currently, there is a lack of study towards the contribution of the BCAA: valine on MASLD. This study investigates the effects of low-dose valine supplementation on MASLD in a high-fat/high-cholesterol diet (HFD) model. Low-dose valine was found to attenuate the progression of MASLD, significantly reducing body weight, liver weight, and eWAT weight, attenuating hyperglycemia and improving serum lipid profiles. It also decreased hyperleptinemia and enhanced hypothalamic leptin sensitivity, leading to reduced food intake. In the eWAT, metabolic flexibility was improved, as indicated by upregulated adipogenesis-related gene expressions and suppressed leptin expression. In the liver, valine improved hepatic leptin sensitivity, alleviated hepatic steatosis, and reduced triglycerides, cholesterol, TNFα, and IL-6 levels. Mechanistically, valine increased hepatic antioxidant capacity and modulated lipid metabolism and antioxidant pathways, downregulating de novo lipogenesis and cholesterol synthesis while increasing fatty acid oxidation, autophagy-related gene expressions. Moreover, hepatic AMPK pathway activity was enhanced, contributing to improved leptin sensitivity and signalling. Additionally, low-dose valine supplementation also modulated the gut microbiome, suggesting a multifaceted approach to managing MASLD.

Hippocampal Leptin Resistance and Cognitive Decline: Mechanisms, Therapeutic Strategies and Clinical Implications

Background: Leptin, an adipokine essential for regulating energy balance, exerts important effects on brain function, notably within the hippocampus, a region integral to learning and memory. Leptin resistance, characterized by diminished responsiveness to elevated leptin levels, disrupts hippocampal function and exacerbates both obesity and cognitive impairments. Scope: This review critically examines how leptin resistance impairs hippocampal synaptic plasticity processes, specifically affecting long-term potentiation (LTP) and long-term depression (LTD), which are crucial for cognitive performance. Findings: Recent research highlights that leptin resistance disrupts N-methyl-D-aspartate (NMDA) receptor dynamics and hippocampal structure, leading to deficits in spatial learning and memory. Additionally, high-fat diets (HFDs), which contribute to leptin resistance, further deteriorate hippocampal function. Potential therapeutic strategies, including leptin sensitizers, show promise in mitigating brain disorders associated with leptin resistance. Complementary interventions such as caloric restriction and physical exercise also enhance leptin sensitivity and offer potential benefits to alleviating cognitive impairments. Aims of the review: This review synthesizes recent findings on the molecular pathways underlying leptin resistance and its impact on synaptic transmission and plasticity in the hippocampus. By identifying potential therapeutic targets, this work aims to provide an integrated approach for addressing cognitive deficits in obesity, ultimately improving the quality of life for affected individuals.

MCM proteins are up-regulated in placentas of women with reduced insulin sensitivity.

In the first trimester of pregnancy the human placenta grows rapidly, making it sensitive to changes in the intrauterine environment. To test whether exposure to an environment in utero often associated with obesity modifies placental proteome and function, we performed untargeted proteomics (LC-MS/MS) in placentas from 19 women (gestational age 35-48 days, i.e. 5+0-6+6 weeks). Maternal clinical traits (body mass index, leptin, glucose, C-peptide and insulin sensitivity) and gestational age were recorded. DNA replication and cell cycle pathways were enriched in the proteome of placentas of women with low maternal insulin sensitivity. Driving these pathways were the minichromosome maintenance (MCM) proteins MCM2, MCM3, MCM4, MCM5, MCM6 and MCM7 (MCM-complex). These proteins are part of the pre-replicative complex and participate in DNA damage repair. Indeed, MCM6 and γH2AX (DNA-damage marker) protein levels correlated in first trimester placental tissue (r = 0.514, P<0.01). MCM6 and γH2AX co-localized to nuclei of villous cytotrophoblast cells, the proliferative cell type of the placenta, suggesting increased DNA damage in this cell type. To mimic key features of the intrauterine obesogenic environment, a first trimester trophoblast cell line, i.e., ACH-3P, was exposed to high insulin (10 nM) or low oxygen tension (2.5% O2). There was a significant correlation between MCM6 and γH2AX protein levels, but these were independent of insulin or oxygen exposure. These findings show that chronic exposure in utero to reduced maternal insulin sensitivity during early pregnancy induces changes in the early first trimester placental proteome. Pathways related to DNA replication, cell cycle and DNA damage repair appear especially sensitive to such an in utero environment.

Reoxygenation improves reduced hypothalamic leptin responsiveness induced by intermittent hypoxia in obese rats

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.

Abstract 41: SerpinA3N in Leptin Receptor Neurons Regulates Metabolic Homeostasis and Cardiovascular Function

Obesity and associated conditions such as type 2 diabetes are among the most concerning health issues in the U.S. Leptin receptor (LepR) signaling in the brain plays a pivotal role in the regulation of food intake and energy expenditure. SerpinA3N is a serine protease inhibitor which is highly expressed in the arcuate nucleus of the hypothalamus, upregulated in diet-induced obesity and by leptin stimulation. However, the role of SerpinA3N in the LepR expressing cells in the control of body weight and glucose homeostasis remain unknown. RNAseq analysis confirmed that SerpinA3N mRNA levels were significantly upregulated in the hypothalamus of mice fed high fat high sucrose diet (HFHSD) for 12 weeks. Using immunofluorescence staining, we confirmed that SerpinA3N is expressed the LepR positive cells of the hypothalamus. Next, we investigated whether loss of SerpinA3N in LepR expressing neurons affects metabolic and glucose homeostasis. For this, we crossed mice harboring floxed alleles of the SerpinA3N gene (SerpinA3N fl/fl ) with mice expressing Cre recombinase driven by the LepR (LepRb Cre ). We found that female, but not male, conditional knockout (CKO, LepRb Cre /SerpinA3N fl/fl ) mice have significantly lower body weight when fed HFHSD. This lower body weight was due to decreased fat mass, measured by NMR. However, no alteration in food intake was observed between female CKO mice and controls, indicating that increased energy expenditure may account for the lower body weight in female CKO mice. Interestingly, CKO mice displayed exaggerated weight loss and anorectic response to leptin treatment (1 mg/g, twice daily, IP), indicating that loss of SerpinA3N enhances leptin sensitivity. Female CKO mice fed normal chow diet also exhibited enhanced insulin sensitivity compared to control animals. On the other hand, male CKO mice displayed significantly improved glucose handling, but no change in insulin sensitivity. Insulin-induced phosphorylation of AKT was elevated only in skeletal muscleof CKO mice relative to controls. Finally, systolic arterial blood pressure of CKO mice fed HFHSD trend to be lower during dark time compared to controls (142±6.4 vs 127.9±7.1 mmHg, p=0.06), although heart rate was not changed. These results demonstrate that SerpinA3N in LepRb-expressing neurons regulate energy and glucose homeostasis in a sex-dependent manner,and may protect from HFHSD induced hypertension.

Improved leptin sensitivity and increased soluble leptin receptor concentrations may underlie the additive effects of combining PYY(3–36) and exendin-4 on body weight lowering in diet-induced obese mice

ObjectiveCo-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. MethodsDiet-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. ResultsWe 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. ConclusionThe 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.

Cel-CS1K: A Celastrol-Chitosan Conjugate for Treating Diet-Induced Obesity.

Celastrol (Cel), extracted from Tripterygium wilfordii Hook, is a potential antiobesity drug, except for its adverse reactions in clinic. In the present study, we synthesized a promising celastrol-chitosan conjugate (Cel-CS1K) and evaluated its antiobesity effect and biological safety in diet-induced obese mice. Cel-CS1K showed higher drug loading (over 10 wt %), good solubility (18-19 mg/mL) in water, slower peak time (Tmax = 4 h), and clearance (T1/2 = 8.97 h) in rats. Cel-CS1K effectively attenuated the cytotoxicity, celastrol-induced apoptosis, and fat accumulation of hepatocytes. Cel-CS1K reduced body weight and dietary amount same as the free Cel but with lower toxicity in blood, liver, and testis. Cel-CS1K improved the glucose homeostasis, HDL-C level, insulin sensitivity, and leptin sensitivity, while it significantly reduced the gene expression levels of LDL-C, TG, and TC in obese mice. Furthermore, the adipose-related gene expression levels provided evidence in support of a role for Cel-CS1K in losing weight by the multimode regulation. Overall, Cel-CS1K provides a translatable therapeutic strategy for the treatment of diet-induced obese humans.

Protein tyrosine phosphatase 1B (PTP1B) function, structure, and inhibition strategies to develop antidiabetic drugs.

Tyrosine protein phosphatase non-receptor type 1 (PTP1B; also known as protein tyrosine phosphatase 1B) is a member of the protein tyrosine phosphatase (PTP) family and is a soluble enzyme that plays an essential role in different physiological processes, including the regulation of metabolism, specifically in insulin and leptin sensitivity. PTP1B is crucial in the pathogenesis of type 2 diabetes mellitus and obesity. These biological functions have made PTP1B validated as an antidiabetic and anti-obesity, and potentially anticancer, molecular target. Four main approaches aim to inhibit PTP1B: orthosteric, allosteric, bidentate inhibition, and PTPN1 gene silencing. Developing a potent and selective PTP1B inhibitor is still challenging due to the enzyme's ubiquitous expression, subcellular location, and structural properties. This article reviews the main advances in the study of PTP1B since it was first isolated in 1988, as well as recent contextual information related to the PTP family to which this protein belongs. Furthermore, we offer an overview of the role of PTP1B in diabetes and obesity, and the challenges to developing selective, effective, potent, bioavailable, and cell-permeable compounds that can inhibit the enzyme.

SerpinA3N in Leptin Receptor Neurons Regulates Metabolic and Glucose Homeostasis

Obesity and associated conditions such as type 2 diabetes are among the most concerning issues for health in the U.S. Leptin receptor signaling in the brain plays a pivotal role in the regulation of food intake and energy expenditure. High fat diet induces inflammation within the hypothalamus, leading to leptin insensitivity which contribute to obesity. Previous studies have shown that a novel gene SerpinA3N, a serine protease inhibitor, which is highly expressed in the arcuate nucleus of the hypothalamus, where the leptin receptor is also highly expressed, is upregulated in diet-induced obesity and by leptin stimulation. However, the role of SerpinA3N in the leptin receptor expressing cells in the control of body weight and glucose homeostasis remain unknown. RNAseq analysis showed that SerpinA3N mRNA levels were significantly upregulated in the hypothalamus of mice fed high fat high sucrose diet (HFHSD) for 12 weeks. Upregulation of hypothalamic SerpinA3N in HFHSD fed mice was confirmed by Western blot. This increase in hypothalamic SerpinA3N appears to be caused by excess of nutrient as we found that exposure to fatty acid significantly increased SerpeinA3N promoter activity in mouse hypothalamic N39 cells. Using immunofluorescence staining, we confirmed that SerpinA3N is expressed the leptin receptor positive cells of the hypothalamus. Next, we investigated whether loss of SerpinA3N in leptin receptor expressing neurons affects metabolic and glucose homeostasis. For this, we crossed mice harboring floxed alleles of the SerpinA3N gene (SerpinA3Nfl/fl) with mice expressing Cre recombinase in leptin receptor cells (LepRCre). We found that female, but not male, conditional knockout (CKO, LepRCre/SerpinA3Nfl/fl) mice have significantly lower body weight when fed normal chow or HFHSD. This lower body weight was due to decreased fat mass, measured by NMR. However, no alteration in food intake was observed between female CKO mice and controls, indicating that increased energy expenditure may account for the lower body weight in female CKO mice. Interestingly, CKO mice displayed exaggerated weight loss and anorectic response following leptin treatment (1 mg/g, twice daily, IP), indicating that loss of SerpinA3N enhances leptin sensitivity. Female CKO mice fed normal chow diet also exhibited enhanced insulin sensitivity compared to control animals. On the other hand, male CKO mice displayed significantly improved glucose handling, but not change in insulin sensitivity, only when fed HFHSD. Finally, insulin-induced phosphorylation of AKT was elevated in skeletal muscle, but not in liver and white adipose tissue, of CKO mice relative to controls. These results demonstrate that SerpinA3N in leptin receptor-expressing neurons regulate body weight and glucose homeostasis in a sex-dependent manner. NIH and VA. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation.

Zinc-alpha2-glycoprotein (AZGP1) has been implicated in peripheral metabolism; however, its role in regulating energy metabolism in the brain, particularly in POMC neurons, remains unknown. Here, we show that AZGP1 in POMC neurons plays a crucial role in controlling whole-body metabolism. POMC neuron-specific overexpression of Azgp1 under high-fat diet conditions reduces energy intake, raises energy expenditure, elevates peripheral tissue leptin and insulin sensitivity, alleviates liver steatosis, and promotes adipose tissue browning. Conversely, mice with inducible deletion of Azgp1 in POMC neurons exhibit the opposite metabolic phenotypes, showing increased susceptibility to diet-induced obesity. Notably, an increase in AZGP1 signaling in the hypothalamus elevates STAT3 phosphorylation and increases POMC neuron excitability. Mechanistically, AZGP1 enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block its ubiquitination degradation. Collectively, these results suggest that AZGP1 plays a crucial role in regulating energy homeostasis and glucose/lipid metabolism by acting on hypothalamic POMC neurons.

Multifaceted role of inosine in complex diseases and human health.

Purines are chemical compounds integral to health and are crucial for the synthesis of nucleic acids. They are part of DNA and RNA and participate in various metabolic and signaling processes. They also function as neurotransmitters and serve as co-substrates for activating many metabolites. Inosine, a purine nucleoside, is a breakdown product of adenosine with similar properties and a much longer half-life (15 h vs ∼5 s) than adenosine. The purpose of this narrative review is to discuss the metabolic effects of inosine and highlight its beneficial properties and implication in complex diseases such as obesity, type 2 diabetes, cancers, cardiovascular diseases, and neurodegenerative diseases. A search was performed for purine- and inosine-related articles on the University of North Carolina (UNC) Health Sciences Library, PubMed, and Google Scholar sites. Inosine is involved in the regulation of RNA editing, metabolic enzyme activity, and signaling pathways. Animal and cell culture studies have shown inosine to be anti-inflammatory, immunomodulatory, and neuroprotective, and serving as a critical regulator of immune checkpoint inhibition therapeutic response in various tumor types. Recent studies have also implicated inosine in increasing energy expenditure, browning of adipose tissue, and improving leptin sensitivity. Human studies, however, have been limited to urate-elevating properties of inosine. These findings make inosine relevant to many complex diseases, and need to be translated to humans. Future studies should be conducted to investigate the mechanisms underlying the role of inosine in adiposity, inflammation, oxidative stress, and neuronal function.

Acupoints catgut embedding recovers leptin resistance via improving autophagy progress mediated by AMPK-mTOR signaling in obese mice

PurposeLeptin resistance represents a primary pathological manifestation in obesity. Investigating potential treatments and associated mechanisms to restore leptin sensitivity is crucial for effective obesity management. This study aimed to explore the therapeutic potential of acupoints catgut embedding (ACE) in addressing obesity and its associated leptin resistance. MethodsA simple obesity model was established by subjecting C57 male mice to a high-fat diet (HFD) for 12 weeks, followed by ACE treatment administered to half of the obese mice for a duration of 4 weeks. The levels of leptin and its receptor-lepRb, were assessed using enzyme-linked immunosorbent assay (ELISA) and Western blot analysis, respectively. Autophagy progression markers were evaluated through quantitative polymerase chain reaction (qPCR) and Western blot analysis. Also, the liver autophagosomes were photographed using electron microscopy. The role of autophagy in regulating leptin resistance was elucidated using an autophagy suppression model. ResultsComparative analyses demonstrated that ACE treatment resulted in a significant reduction in body weight and blood lipid levels compared to the HFD group. Furthermore, serum leptin levels decreased, while liver lepRb expression increased following ACE treatment. The mRNA and protein expression levels of autophagy in liver were adjusted by ACE treatment. Interestingly, the beneficial effects of ACE were attenuated upon the administration of an autophagy inhibitor. Additionally, ACE treatment led to the activation of the AMPK-mTOR signaling pathway, a crucial regulator of autophagy. ConclusionThese findings suggest that ACE therapy holds promise for recovering leptin resistance by enhancing autophagy progression, mediated via the AMPK-mTOR signaling pathway in liver.

A negative feedback loop between TET2 and leptin in adipocyte regulates body weight

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.

Central inhibition of HDAC6 re-sensitizes leptin signaling during obesity to induce profound weight loss

Leptin resistance during excess weight gain significantly contributes to the recidivism of obesity to leptin-based pharmacological therapies. The mechanisms underlying the inhibition of leptin receptor (LepR) signaling during obesity are still elusive. Here, we report that histone deacetylase 6 (HDAC6) interacts with LepR, reducing the latter's activity, and that pharmacological inhibition of HDAC6 activity disrupts this interaction and augments leptin signaling. Treatment of diet-induced obese mice with blood-brain barrier (BBB)-permeable HDAC6 inhibitors profoundly reduces food intake and leads to potent weight loss without affecting the muscle mass. Genetic depletion of Hdac6 in Agouti-related protein (AgRP)-expressing neurons or administration with BBB-impermeable HDAC6 inhibitors results in a lack of such anti-obesity effect. Together, these findings represent the first report describing a mechanistically validated and pharmaceutically tractable therapeutic approach to directly increase LepR activity as well as identifying centrally but not peripherally acting HDAC6 inhibitors as potent leptin sensitizers and anti-obesity agents.

Loss of GIPR in LEPR cells impairs glucose control by GIP and GIP:GLP-1 co-agonism without affecting body weight and food intake in mice

ObjectiveThe glucose-dependent insulinotropic polypeptide (GIP) decreases body weight via central GIP receptor (GIPR) signaling, but the underlying mechanisms remain largely unknown. Here, we assessed whether GIP regulates body weight and glucose control via GIPR signaling in cells that express the leptin receptor (Lepr). MethodsHypothalamic, hindbrain, and pancreatic co-expression of Gipr and Lepr was assessed using single cell RNAseq analysis. Mice with deletion of Gipr in Lepr cells were generated and metabolically characterized for alterations in diet-induced obesity (DIO), glucose control and leptin sensitivity. Long-acting single- and dual-agonists at GIPR and GLP-1R were further used to assess drug effects on energy and glucose metabolism in DIO wildtype (WT) and Lepr-Gipr knock-out (KO) mice. ResultsGipr and Lepr show strong co-expression in the pancreas, but not in the hypothalamus and hindbrain. DIO Lepr-Gipr KO mice are indistinguishable from WT controls related to body weight, food intake and diet-induced leptin resistance. Acyl-GIP and the GIPR:GLP-1R co-agonist MAR709 remain fully efficacious to decrease body weight and food intake in DIO Lepr-Gipr KO mice. Consistent with the demonstration that Gipr and Lepr highly co-localize in the endocrine pancreas, including the β-cells, we find the superior glycemic effect of GIPR:GLP-1R co-agonism over single GLP-1R agonism to vanish in Lepr-Gipr KO mice. ConclusionsGIPR signaling in cells/neurons that express the leptin receptor is not implicated in the control of body weight or food intake, but is of crucial importance for the superior glycemic effects of GIPR:GLP-1R co-agonism relative to single GLP-1R agonism.

A celastrol-loaded DNA nano-patroller regulates hypothalamus leptin sensitivity and adipose energy expenditure for anti-obesity therapy

Obesity is a chronic metabolic disease mainly caused by fat accumulation. Well-recognized anti-obesity therapies are lacking. Celastrol is a bioactive small-molecule drug extracted from the roots of Tripterygium Wilfordii, which has excellent anti-obesity efficacy. However, the low bioavailability and permeability of celastrol limit its clinical applications. Meanwhile, tetrahedral framework nucleic acid (tFNA) represents a nucleic acid nanomaterial with suitable biocompatibility and tissue and cell permeability. Therefore, this study aimed to use tFNA as a delivery carrier for celastrol for the first time. tFNA efficiently loaded celastrol with proper stability and in vivo bio-distribution. Celastrol-loaded tFNA simultaneously rescued leptin resistance in the hypothalamus and promoted energy expenditure in adipose tissues, acting as a systemic “nano-patroller” in search of various abnormal conditions. Compared to the celastrol monomer, celastrol-loaded tFNA exerted superior inhibitory effects on fat accumulation, obesity, inflammation, and insulin resistance. In conclusion, tFNA is a promising tool for deeper anti-obesity applications of celastrol.

Conditional Deletion of β-Catenin in the Mediobasal Hypothalamus Impairs Adaptive Energy Expenditure in Response to High-Fat Diet and Exacerbates Diet-Induced Obesity.

β-Catenin is a bifunctional molecule that is an effector of the wingless-related integration site (Wnt) signaling to control gene expression and contributes to the regulation of cytoskeleton and neurotransmitter vesicle trafficking. In its former role, β-catenin binds transcription factor 7-like 2 (TCF7L2), which shows strong genetic associations with the pathogenesis of obesity and type-2 diabetes. Here, we sought to determine whether β-catenin plays a role in the neuroendocrine regulation of body weight and glucose homeostasis. Bilateral injections of adeno-associated virus type-2 (AAV2)-mCherry-Cre were placed into the arcuate nucleus of adult male and female β-catenin flox mice, to specifically delete β-catenin expression in the mediobasal hypothalamus (MBH-β-cat KO). Metabolic parameters were then monitored under conditions of low-fat (LFD) and high-fat diet (HFD). On LFD, MBH-β-cat KO mice showed minimal metabolic disturbances, but on HFD, despite having only a small difference in weekly caloric intake, the MBH-β-cat KO mice were significantly heavier than the control mice in both sexes (p < 0.05). This deficit seemed to be due to a failure to show an adaptive increase in energy expenditure seen in controls, which served to offset the increased calories by HFD. Both male and female MBH-β-cat KO mice were highly glucose intolerant when on HFD and displayed a significant reduction in both leptin and insulin sensitivity compared with controls. This study highlights a critical role for β-catenin in the hypothalamic circuits regulating body weight and glucose homeostasis and reveals potential mechanisms by which genetic variation in this pathway could impact on development of metabolic disease.

Hypothalamic P62 (SQSTM1) regulates energy balance by modulating leptin signaling.

The multifaceted functions of p62 (SQSTM1) are increasingly recognized, but its role in hypothalamic metabolism-associated neurons for energy balance has yet to be elucidated. Single-nucleus RNA sequencing (snRNA-Seq) was performed on hypothalamic tissues from db/db and db/m mice to explore p62 expression. Overexpression and knockout of p62 in hypothalamic POMC neurons were performed via AAV-mediated gene delivery and Cre-loxP systems. Metabolic outcomes were assessed under normal chow (NCD) and high-fat diet (HFD) conditions. The co-immunoprecipitation and luciferase reporter assays were used to investigate the interaction between p62 and STAT3. The snRNA-Seq analysis found that p62 was ubiquitously expressed in hypothalamic neurons, with significantly higher levels in POMC neurons of db/db mice compared to db/m controls. Under NCD or HFD conditions, the absence of p62 in POMC neurons led to increased body weight, decreased energy expenditure and leptin sensitivity, while its overexpression in POMC neurons produced the opposite phenotype. Mechanistically, p62 interacts with STAT3, facilitating its phosphorylation to initiate POMC transcription and amplify leptin sensitivity. This study demonstrated the capacity of p62 to monogenically regulate the obesity phenotype and emphasized its dual role in managing energy homeostasis through direct modulation of STAT3/POMC signaling and amplification of leptin sensitivity.

The Mechanism of Leptin Resistance in Obesity and Therapeutic Perspective.

Leptin resistance is induced via leptin signaling blockade by chronic overstimulation of the leptin receptor and intracellular signaling defect or increased hypothalamic inflammation and suppressor of cytokine signaling (SOCS)-3 expression. High-fat diet triggers leptin resistance induced by at least two independent causes: first, the limited ability of peripheral leptin to activate hypothalamic signaling transducers and activators of transcription (STAT) signaling and secondly a signaling defect in leptin-responsive hypothalamic neurons. Central leptin resistance is dependent on decreased leptin transport efficiency across the blood brain barrier (BBB) rather than hypothalamic leptin insensitivity. Since the hypothalamic phosphorylated STAT3 (pSTAT3) represents a sensitive and specific readout of leptin receptor-B signaling, the assessment of pSTAT3 levels is the gold standard. Hypertriglyceridemia is one of important factors to inhibit the transport of leptin across BBB in obesity. Mismatch between high leptin and the amount of leptin receptor expression in obesity triggers brain leptin resistance via increasing hypothalamic inflammation and SOCS-3 expression. Therapeutic strategies that regulate the passage of leptin to the brain include the development of modifications in the structure of leptin analogues as well as the synthesis of new leptin receptor agonists with increased BBB permeability. In the hyperleptinemic state, polyethylene glycol (PEG)-modified leptin is unable to pass through the BBB. Peripheral histone deacetylase (HDAC) 6 inhibitor, tubastatin, and metformin increase central leptin sensitization. While add-on therapy with anagliptin, metformin and miglitol reduce leptin concentrations, the use of long-acting leptin analogs, and exendin-4 lead to the recovery of leptin sensitivity. Contouring surgery with fat removal, and bariatric surgery independently of the type of surgery performed provide significant improvement in leptin concentrations. Although approaches to correcting leptin resistance have shown some success, no clinically effective application has been developed to date. Due to the impairment of central and peripheral leptin signaling, as well as the extensive integration of leptin-sensitive metabolic pathways with other neurons, the effectiveness of methods used to eliminate leptin resistance is extremely limited.

Glucagon-Like Peptide-1 (GLP-1) during Ramadan: Narrative Review of the Published Literature.

Ramadan fasting, a religious practice observed by Muslims worldwide, involves abstaining from eating, drinking, smoking, and using oral medications from dawn to dusk during the ninth lunar month. Studies have demonstrated that fasting during Ramadan has been shown to increase HDL cholesterol, leptin, adiponectin, and insulin sensitivity, as well as lower several hemostatic risk factors for cardiovascular diseases. Additionally, it may result in a drop in blood sugar levels, especially in diabetics who are also on blood sugar-lowering medicine. Hypoglycemia, characterized by low blood sugar levels, could also result from fasting during Ramadan. The GLP-1 (glucagon-like peptide-1) hormone plays a significant role in regulating glucose metabolism and insulin secretion, and Ramadan fasting can affect its production and release in the gut. Research contributes to our understanding of the utilization of GL-1 medications during Ramadan among patients, broadening therapy alternatives and offering insightful information for well-informed decision-making. Therefore, this narrative review aims to explore the current evidence that studies the safety and efficacy of GLP-1 agonists during Ramadan for nondiabetic and diabetic patients to ensure healthy fasting during Ramadan.