Search

Craniopharyngioma (CP) is a benign tumor with a high rate of obesity and frequent recurrence. Moreover, the role of leptin/leptin receptors axis in obesity and the prognosis of CP is still unknown. Plasma leptin concentration and mRNA expression of leptin receptors were assessed in patients with CP. Moreover, the association between leptin/leptin receptors axis, weight-related outcomes, and progression-free survival (PFS) were explored in CP patients. Leptin receptors overexpressed in CP tumor tissue were compared to normal brain tissue (p < 0.05); compared to healthy controls, the concentration of leptin was elevated in CP with or without matched age, sex, and body mass index (BMI) (p < 0.05). The high plasma leptin level was an independent risk predictor for significant weight gain (adjusted odds ratio (aOR) = 2.29, and p = 0.030) and new-onset obesity (aOR = 6.64, and p = 0.016). High plasma leptin level (adjusted hazard ratio (aHR) = 3.74, and p = 0.011) and leptin receptor (LEPR) mRNA expression (aHR = 3.12, and p = 0.045) were independent risk factors for poor PFS in CP. Inappropriately elevated leptin relative to BMI and its failure to inhibit further weight gain indicate the existence of leptin resistance in patients with CP. Leptin and LEPR were independent predictors for PFS of patients with CP. The leptin/leptin receptors axis may be a potential therapeutic target for obesity in patients with CP.

Tesis CEINDO, Universidad San Pablo CEU, Programa de doctorado "Ciencia y tecnología de la salud". Leída el 24 de abril de 2023 Los receptores de leptina, una hormona liberada por el tejido adiposo (TA), se expresan por todo el sistema nervioso central. Así mismo, el consumo de dietas ricas en grasas produce un desequilibrio en el TA que conduce a hiperleptinemia, situación capaz de desensibilizar el receptor de leptina (RLep) y conducir a deterioro cognitivo. El objetivo de este trabajo ha sido identificar la influencia de las grasas saturadas (SOLF) y monoinsaturadas (UOLF) en la funcionalidad del RLep en TA, hipotálamo e hipocampo. Para ello, se han alimentado ratones con SOLF/UOLF durante 8 semanas. Nuestros resultados muestran que SOLF y UOLF deterioran la plasticidad sináptica, aunque sólo SOLF produce deterioro de la memoria espacial. Respecto a la señalización del RLep en el hipocampo, SOLF altera la vía de la STAT3, mientras que UOLF desensibiliza las vías de la Akt y la AMPK. En cambio, en el hipotálamo, estas dos vías se bloquean por la dieta SOLF. En el TA, aunque la expresión de leptina solo aumenta con UOLF, SOLF desacopla el RLep de las vías STAT3, Akt y AMPK. En conclusión, nuestro estudio demuestra que la composición de la dieta determina el grado de disfunción hipocampal y de resistencia a leptina. Leptin receptors, a hormone released by adipose tissue (AT), are expressed throughout the central nervous system. Likewise, the consumption of high-fat diets produces an imbalance in AT leading to hyperleptinaemia, a situation capable of desensitising the leptin receptor (LepR) and leading to cognitive impairment. The aim of this study was to identify the influence of saturated (SOLF) and monounsaturated (UOLF) fats on the functionality of LepR in AT, hypothalamus and hippocampus. To do this, mice were fed SOLF/UOLF for 8 weeks. Our results show that SOLF and UOLF impair synaptic plasticity, although only SOLF causes impairment of spatial memory. Regarding LepR signalling in the hippocampus, SOLF disrupts the STAT3 pathway, while UOLF desensitises the Akt and AMPK pathways. In contrast, in the hypothalamus, these two pathways are blocked by SOLF. In the AT, although leptin expression is only increased by UOLF, SOLF uncouples LepR from the STAT3, Akt and AMPK pathways. In conclusion, our study demonstrates that diet composition determines the degree of hippocampal dysfunction and leptin resistance.

The prevalence of obesity is on the rise. What was once considered a simple disease of energy imbalance is now recognized as a complex condition perpetuated by neuro- and immunopathologies. In this review, we summarize the current knowledge of the neuroimmunoendocrine mechanisms underlying obesity. We examine the pleiotropic effects of leptin action in addition to its established role in the modulation of appetite, and we discuss the neural circuitry mediating leptin action and how this is altered with obesity, both centrally (leptin resistance) and in adipose tissues (sympathetic neuropathy). Finally, we dissect the numerous causal and consequential roles of adipose tissue macrophages in obesity and highlight recent key studies demonstrating their direct role in organismal energy homeostasis.

SummaryIn obesity, anorectic responses to leptin are diminished, giving rise to the concept of “leptin resistance.” Increased expression of protein tyrosine phosphatase 1B (PTP1B) has been associated with the attenuation of leptin signaling and development of cellular leptin resistance. Here we report that hypothalamic levels of the tyrosine phosphatase TCPTP are also elevated in obesity to attenuate the leptin response. We show that mice that lack TCPTP in neuronal cells have enhanced leptin sensitivity and are resistant to high-fat-diet-induced weight gain and the development of leptin resistance. Also, intracerebroventricular administration of a TCPTP inhibitor enhances leptin signaling and responses in mice. Moreover, the combined deletion of TCPTP and PTP1B in neuronal cells has additive effects in the prevention of diet-induced obesity. Our results identify TCPTP as a critical negative regulator of hypothalamic leptin signaling and causally link elevated TCPTP to the development of cellular leptin resistance in obesity.

High-fat diets enriched with lauric acid (SOLF) do not enhance leptin production despite expanding white adipose tissue (WAT). Our study aimed at identifying the influence of SOLF vs. oleic acid-enriched diets (UOLF) on the autoparacrine effect of leptin and was carried out on eight-week-old mice consuming control chow, UOLF or SOLF. Phosphorylation of kinases integral to leptin receptor (LepR) signalling pathways (705Tyr-STAT3, 473Ser-Akt, 172Thr-AMPK), adipocyte-size distribution, fatty acid content, and gene expression were analyzed in WAT. SOLF enhanced basal levels of phosphorylated proteins but reduced the ability of leptin to enhance kinase phosphorylation. In contrast, UOLF failed to increase basal levels of phosphorylated proteins and did not modify the effect of leptin. Both SOLF and UOLF similarly affected adipocyte-size distribution, and the expression of genes related with adipogenesis and inflammation. WAT composition was different between groups, with SOLF samples mostly containing palmitic, myristic and lauric acids (>48% w/w) and UOLF WAT containing more than 80% (w/w) of oleic acid. In conclusion, SOLF appears to be more detrimental than UOLF to the autoparacrine leptin actions, which may have an impact on WAT inflammation. The effect of SOLF and UOLF on WAT composition may affect WAT biophysical properties, which are able to condition LepR signaling.

Obesity is a growing worldwide health problem, affecting many people due to excessive saturated fat consumption, lack of exercise, or a sedentary lifestyle. Leptin is an adipokine secreted by adipose tissue that increases in obesity and has central actions not only at the hypothalamic level but also in other regions and nuclei of the central nervous system (CNS) such as the cerebral cortex and hippocampus. These regions express the long form of leptin receptor LepRb, which is the unique leptin receptor capable of transmitting complete leptin signaling, and are the first regions to be affected by chronic neurocognitive deficits, such as mild cognitive impairment (MCI) and Alzheimer’s Disease (AD). In this review, we discuss different leptin resistance mechanisms that could be implicated in increasing the risk of developing AD, as leptin resistance is frequently associated with obesity, which is a chronic low-grade inflammatory state, and obesity is considered a risk factor for AD. Key players of leptin resistance are SOCS3, PTP1B, and TCPTP whose signalling is related to inflammation and could be worsened in AD. However, some data are controversial, and it is necessary to further investigate the underlying mechanisms of the AD-causing pathological processes and how altered leptin signalling affects such processes.

Leptin is an adipokine with a pleiotropic impact on many physiological processes, including hypothalamic-pituitary-somatotropic (HPS) axis activity, which plays a key role in regulating mammalian metabolism. Leptin insensitivity/resistance is a pathological condition in humans, but in seasonal animals, it is a physiological adaptation. Therefore, these animals represent a promising model for studying this phenomenon. This study aimed to determine the influence of leptin on the activity of the HPS axis. Two in vivo experiments performed during short- and long-day photoperiods were conducted on 12 ewes per experiment, and the ewes were divided randomly into 2 groups. The arcuate nucleus, paraventricular nucleus, anterior pituitary (AP) tissues, and blood were collected. The concentration of growth hormone (GH) was measured in the blood, and the relative expression of GHRH, SST, GHRHR, SSTR1, SSTR2, SSTR3, SSTR5, LEPR, and GH was measured in the collected brain structures. The study showed that the photoperiod, and therefore leptin sensitivity, plays an important role in regulating HPS axis activity in the seasonal ewe. However, leptin influences the release of GH in a season-dependent manner, and its effect seems to be targeted at the posttranscriptional stages of GH secretion.

This study examined how leptin affects growth hormone (GH) release and investigated the effects of leptin, GH, and day length on the suppressor of cytokine signaling-3 (SOCS-3) mRNA levels in the adenohypophyses of sheep. The study consisted of two experiments. The first experiment was conducted during long (LD) and short (SD) days. Within-season and replicate sheep were centrally infused with Ringer-Locke buffer or leptin three times at 60-min intervals at the beginning of experiments. The second experiment involved adenohypophyses collected from sheep that were euthanized in May or November. Pituitary explants were treated with medium alone (Control) or medium with leptin or GH at different concentrations and incubated for various times. The results of the first experiment indicated GH concentrations were seasonally dependent and that leptin had no effect on GH secretion. The results of the second experiment indicated a stronger influence of leptin on the expression of SOCS-3 during the SD season than the LD season. During SDs, significant effects of both GH doses on SOCS-3 expression were observed. These results indicate a strong association between leptin, GH, and SOCS-3, which may explain the disruption of SOCS-3 leptin and GH signaling and the dominant effect of photoperiod on the above relationships.

Obesity and type 2 diabetes mellitus (T2DM) are preconditions for the development of metabolic syndrome, which is reaching pandemic levels worldwide, but there are still only a few anti-obesity drugs available. One of the promising tools for the treatment of obesity and related metabolic complications is anorexigenic peptides, such as prolactin-releasing peptide (PrRP). PrRP is a centrally acting neuropeptide involved in food intake and body weight (BW) regulation. In its natural form, it has limitations for peripheral administration; thus, we designed analogs of PrRP lipidized at the N-terminal region that showed high binding affinities, increased stability and central anorexigenic effects after peripheral administration. In this review, we summarize the preclinical results of our chronic studies on the pharmacological role of the two most potent palmitoylated PrRP31 analogs in various mouse and rat models of obesity, glucose intolerance, and insulin resistance. We used mice and rats with diet-induced obesity fed a high-fat diet, which is considered to simulate the most common form of human obesity, or rodent models with leptin deficiency or disrupted leptin signaling in which long-term food intake regulation by leptin is distorted. The rodent models described in this review are models of metabolic syndrome with different severities, such as obesity or morbid obesity, prediabetes or diabetes and hypertension. We found that the effects of palmitoylated PrRP31 on food intake and BW but not on glucose intolerance require intact leptin signaling. Thus, palmitoylated PrRP31 analogs have potential as therapeutics for obesity and related metabolic complications.

Leptin promotes satiety and modulates energy balance and weight. Diet-induced obesity leads to leptin resistance, exacerbating overeating. We reviewed the literature on the relationship between diet and leptin, which suggests that addressing leptin resistance through dietary interventions can contribute counteracting obesity. Albeit some limitations (e.g., limited rigor, small samples sizes), studies in animals and humans show that diets high in fat, carbohydrates, fructose, and sucrose, and low in protein are drivers of leptin resistance. Despite methodological heterogeneity pertaining to this body of literature, experimental studies show that energy-restricted diets can reduce leptinemia both in the short and long term and potentially reverse leptin resistance in humans. We also discuss limitations of this evidence, future lines of research, and implications for clinical and public health translations. Main limitations include the lack of a single universally-accepted definition of leptin resistance, and of adequate ways to accurately measure it in humans. The use of leptin sensitizers (drugs) and genetically individualized diets are alternatives against leptin resistance that should be further researched in humans. The tested very-low-energy intervention diets are challenging to translate into wide clinical or population recommendations. In conclusion, the link between nutritional components and leptin resistance, as well as research indicating that this condition is reversible, emphasizes the potential of diet to recover sensitivity to this hormone. A harmonized definition of leptin resistance, reliable methods to measure it, and large-scale, translational, clinical, and precision nutrition research involving rigorous methods are needed to benefit populations through these approaches.

To update information about comorbidity of non-alcoholic fatty liver disease (NAFLD) and gallstones disease (GD), evaluation of clinical and laboratory data, including insulin, leptin and adiponectin in individuals with NAFLD in combination with GD.According to the design, we conducted an open comparative study of 169 patients with NAFLD. The following comparison groups were formed: group 1 (n=95) patients with NAFLD without GD, group 2 (n=35) patients with NAFLD and GD and group 3 (n=39) patients with NAFLD, GD and previous cholecystectomy.A high prevalence of coronary heart disease was found in the group of patients with GD and cholecystectomy (2=6.198,p0.05); positive, statistically significant correlation relationships of cholelithiasis, cholecystectomy with ischemic heart disease (rs=0.172,p0.05 andrs=0.241,p0.05, respectively). There was a statistically significant decrease in total bilirubin and total protein in patients of group 3 (H=7.376,p0.03 and H=6.345,p0.04). The level of leptin is statistically significantly higher and positively interrelated with cholecystectomy (H=5.812,p0.05,rs=0.313,p0.05).Patients with NAFLD, GD and previous cholecystectomy have a high prevalence of coronary heart disease; the phenomenon of insulin and leptin resistance, high level of adiponectin were revealed in patients with NAFLD and gallstones; hyperleptinemia was observed among patients with NAFLD, GD after cholecystectomy.Цель исследования.Актуализация информации о коморбидности неалкогольной жировой болезни печени (НАЖБП) и желчнокаменной болезни (ЖКБ), оценка клинических, лабораторных данных, в том числе уровней инсулина, лептина и адипонектина, у лиц с НАЖБП в сочетании с ЖКБ. Материалы и методы.Согласно дизайну нами проведено открытое сравнительное исследование с включением 169 пациентов с НАЖБП. Сформированы следующие группы сравнения: группа 1 (n=95) пациенты с НАЖБП без ЖКБ, группа 2 (n=35) пациенты с НАЖБП и ЖКБ с сохраненным желчным пузырем и группа 3 (n=39) пациенты с НАЖБП и ЖКБ, перенесшие холецистэктомию. Результаты.Выявлена высокая распространенность ишемической болезни сердца (ИБС) в группе пациентов с ЖКБ, перенесших холецистэктомию (2=6,198;p0,05), обнаружены положительные статистически значимые корреляционные взаимосвязи ЖКБ, перенесенной холецистэктомии с ИБС (rs=0,172,p0,05 иrs=0,241,p0,05, соответственно). Отмечалось статистически значимое снижение уровня общего билирубина и общего белка у пациентов 3-й группы (H=7,376,p0,03 и H=6,345,p0,04). Уровень лептина статистически значимо выше и положительно взаимосвязан с холецистэктомией по результатам сравнительного и корреляционного анализа (H=5,812,p0,05,rs=0,313,p0,05). Заключение.Пациенты с НАЖБП, ЖКБ и перенесенной холецистэктомией имеют высокую распространенность ИБС; у пациентов, страдающих НАЖБП и ЖКБ, выявлен феномен инсулино- и лептинорезистентности, высокий уровень адипонектина; гиперлептинемия отмечена среди больных НАЖБП с ЖКБ после холецистэктомии.

Leptin resistance in endothelial cells leads to vascular endothelial dysfunction, which is the beginning and crucial link of atherosclerosis. However, the mechanism of leptin resistance remains obscure. Acid sphingomyelinase (ASM) catalyzes the hydrolysis of sphingomyelin to produce ceramide, which plays an important role in the progression of metabolic and cardiovascular diseases. In this study, we investigated whether ASM could regulate leptin resistance in vascular endothelial cells. We induced endothelial leptin resistance in rat aortic endothelial cells through treatment with palmitic acid (0.3 mM) or knockdown of leptin receptor (Ob-Rb), which resulted in the increase of suppressor of cytokine signaling 3 expression, the decrease of Ob-Rb expression, and signal transducer and activator of transcription 3 (STAT3) phosphorylation at Tyr705. We found that these indicators of leptin resistance were reversed by knockdown of ASM or by the selective ASM inhibitors amitriptyline (AMI) and imipramine (IMI). Supplementation of ceramide inhibited Ob-Rb expression and STAT3 phosphorylation by inhibiting extracellular signal-regulated kinase 1/2 activation. Furthermore, we found that knockdown of ASM enhanced endothelial nitric oxide (NO) synthase activity and NO production, as well as the Akt phosphorylation at ser473, which was regulated by STAT3. High-fat diet (HFD) feeding-induced leptin resistance in rats in vivo; administration of AMI and IMI (10 mg· kg−1 per day, intraperitoneally, for 2 weeks) increased the release of endothelial NO to relieve the vasodilatory response and improved the endothelial leptin resistance in the aorta of HFD-fed rats. These results suggest that ASM downregulation reverses endothelial leptin resistance, and consequently improves vascular endothelial dysfunction. This study highlighted ASM as a potential therapeutic target for endothelial leptin resistance.

Aim: Leptin is produced by the adipose tissue and reduces body weight by decreasing appetite and increasing metabolism. Patients treated with antipsychotics often have treatment-induced weight-gain, leading to other metabolic complications. Obese subjects often have leptin resistance, which is defined as the presence of hyperleptinemia in obesity. We evaluated leptin resistance in subjects with schizophrenia in comparison with healthy controls of similar body composition. Methods: We determined fasting serum leptin levels and body composition parameters in 30 subjects with schizophrenia and 30 healthy, age- and sex-matched controls. Both groups were of comparable amount of body fat and lean body mass. Leptin resistance was measured as the ratio between resting energy expenditure (REE, calculated using the results of body composition analysis) and the leptin level. Results: There was no difference in the level of fasting serum leptin between the patients and the control group; there were also no differences between men in the schizophrenia and in the control groups and between women in the schizophrenia and in the control groups. Women had a significantly higher level of leptin in the schizophrenia group, in the control group and in the whole study sample (p < 0.001 for all comparisons). REE was comparable between both study groups. REE was higher in men in the whole study sample and in both study groups (p < 0.001 for all comparisons). The REE:leptin ratio did not differ between both groups. As above, the REE:leptin ratio was significantly higher in men in the schizophrenia group, in the control group and in the whole study sample (p < 0.001 for all comparisons). Conclusion: We found no differences in REE, fasting serum leptin levels and leptin resistance. However, certain differences in leptin resistance between schizophrenia patients and healthy controls may play a role in weight gain induced by antipsychotics.

Insensitivity to the antiobesity hormone, leptin, has been suggested to be involved in the pathogenesis of obesity. However, the pathological mechanisms underlying the development of leptin resistance are not well-understood. This study aimed to examine the pathological mechanisms of leptin resistance in obesity. In the present study, we found that 4-hydroxy-2-nonenal (4-HNE), an aldehyde, may be involved in the development of leptin resistance. The SH-SY5Y-Ob-Rb human neuroblastoma cell line, transfected to express the Ob-Rb leptin receptor stably, was treated with 4-HNE, and leptin-induced signal transduction was analyzed. We found that 4-HNE dose- and time-dependently inhibited leptin-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation, a major antiobesity signal of leptin. On the other hand, 4-HNE did not affect tyrosine phosphorylation of broad cellular proteins, suggesting that the inhibitory effect may be selective to leptin signaling. Mechanistically, 4-HNE induced the eukaryotic initiation factor 2α-CCAAT/enhancer-binding protein homologous protein arm of endoplasmic reticulum stress signaling, which may be involved in the pathogenesis of leptin resistance. Overall, these results suggest that 4-HNE may partly affect endoplasmic reticulum stress-induced unfolded protein response signaling and may be involved in the pathogenesis of leptin resistance.

The hypothesis advanced is that endospanin, a highly conserved vesicle traffic protein in vertebrates, regulates leptin sensitivity in bone signaling. The effects of leptin on bones are well-studied but without consensus on whether the increases in leptin signaling stimulate bone gain or loss. The bone response may depend on leptin sensitivity, and endospanin is an established modulator of leptin sensitivity. An argument is advanced to develop zebrafish models for specific leptin signaling pathways. Zebrafish have well-developed molecular tools (e.g., CRISPR) and the advantage of non-destructive sampling of bones in the form of scales. Using these tools, experiments are described to substantiate the role of endospanin in zebrafish bone dynamics.

Previous studies have shown that agonists of GPR17 stimulate, while antagonists inhibit feeding. However, whole body knockout of GPR17 in mice of the C57Bl/6 strain did not affect energy balance, whereas selective knockout in oligodendrocytes or pro-opiomelanocortin neurons provided protection from high fat diet-induced obesity and impaired glucose homeostasis. We reasoned that whole body knockout of GPR17 in mice of the 129 strain might elicit more marked effects because the 129 strain is more susceptible than the C57Bl/6 strain to increased sympathetic activity and less susceptible to high fat diet-induced obesity. Consistent with this hypothesis, compared to wild-type mice, and when fed on either a chow or a high fat diet, GPR17 -/- mice of the 129 strain displayed increased expression of uncoupling protein-1 in white adipose tissue, lower body weight and fat content, reduced plasma leptin, non-esterified fatty acids and triglycerides, and resistance to high fat diet-induced glucose intolerance. Not only energy expenditure, but also energy intake was raised. Administration of leptin did not suppress the increased food intake in GPR17 -/- mice of the 129 strain, whereas it did suppress food intake in GPR17 +/+ mice. The only difference between GPR17 +/- and GPR17 +/+ mice of the C57Bl/6 strain was that the body weight of the GPR17 -/- mice was lower than that of the GPR17 +/+ mice when the mice were fed on a standard chow diet. We propose that the absence of GPR17 raises sympathetic activity in mice of the 129 strain in response to a low plasma fuel supply, and that the consequent loss of body fat is partly mitigated by increased energy intake.

Ceramide-induced mitochondrial fission drives high-fat diet (HFD)-induced obesity. However, molecules targeting mitochondrial dynamics have shown limited benefits in murine obesity models. Here, we reveal that these compounds are either unable to block ceramide-induced mitochondrial fission or require extended incubation periods to be effective. In contrast, targeting endolysosomal trafficking events important for mitochondrial fission rapidly and robustly prevented ceramide-induced disruptions in mitochondrial form and function. By simultaneously inhibiting ARF6- and PIKfyve-dependent trafficking events, the synthetic sphingolipid SH-BC-893 blocked palmitate- and ceramide-induced mitochondrial fission, preserved mitochondrial function, and prevented ER stress invitro. Similar benefits were observed in the tissues of HFD-fed mice. Within 4h of oral administration, SH-BC-893 normalized mitochondrial morphology in the livers and brains of HFD-fed mice, improved mitochondrial function in white adipose tissue, and corrected aberrant plasma leptin and adiponectin levels. As an interventional agent, SH-BC-893 restored normal body weight, glucose disposal, and hepatic lipid levels in mice consuming a HFD. In sum, the sphingolipid analog SH-BC-893 robustly and acutely blocks ceramide-induced mitochondrial dysfunction, correcting diet-induced obesity and its metabolic sequelae.

The adipocyte-derived ‘satiety promoting’ hormone, leptin, has been identified as a key central regulator of body weight and fertility, such that its absence leads to obesity and infertility. Plasma leptin levels reflect body adiposity, and therefore act as an ‘adipostat’, whereby low leptin levels reflect a state of low body adiposity (under-nutrition/starvation) and elevated leptin levels reflect a state of high body adiposity (over-nutrition/obesity). While genetic leptin deficiency is rare, obesity-related leptin resistance is becoming increasingly common. In the absence of adequate leptin sensitivity, leptin is unable to exert its ‘anti-obesity’ effects, thereby exacerbating obesity. Furthermore, extreme leptin resistance and consequent low or absent leptin signalling resembles a state of starvation and can thus lead to infertility. However, leptin resistance occurs on a spectrum, and it is possible to be resistant to leptin’s metabolic effects while retaining leptin’s permissive effects on fertility. This may be because leptin exerts its modulatory effects on energy homeostasis and reproductive function through discrete intracellular signalling pathways, and these pathways are differentially affected by the molecules that promote leptin resistance. This review discusses the potential mechanisms that enable leptin to exert differential control over metabolic and reproductive function in the contexts of healthy leptin signalling and of diet-induced leptin resistance.

Ceramide‐induced mitochondrial fission drives high‐fat diet (HFD)‐induced obesity. However, molecules targeting mitochondrial dynamics have shown limited benefits in murine obesity models. Here, we reveal that these compounds are either unable to block ceramide‐induced mitochondrial fission or require extended incubation periods to be effective. In contrast, targeting endolysosomal trafficking events important for mitochondrial fission rapidly and robustly prevented ceramide‐induced disruptions in mitochondrial form and function. By simultaneously inhibiting ARF6‐ and PIKfyve‐dependent trafficking events, the synthetic sphingolipid SH‐BC‐893 blocked palmitate‐ and ceramide‐induced mitochondrial fission, preserved mitochondrial function, and prevented ER stress in vitro. Similar benefits were observed in the tissues of HFD‐fed mice. Within 4 h of oral administration, SH‐BC‐893 normalized mitochondrial morphology in the livers and brains of HFD‐fed mice, improved mitochondrial function in white adipose tissue, and corrected aberrant plasma leptin and adiponectin levels. As an interventional agent, SH‐BC‐893 restored normal body weight, glucose disposal, and hepatic lipid levels in mice consuming a HFD. In sum, the sphingolipid analog SH‐BC‐893 robustly and acutely blocks ceramide‐induced mitochondrial dysfunction, correcting diet‐induced obesity and its metabolic sequelae., Ceramide‐induced mitochondrial fission drives diet‐induced obesity and its metabolic sequelae. Here, a small molecule targeting endocytic trafficking was found to block mitochondrial fission and reverse high fat diet‐induced obesity and metabolic dysfunction in mice.

Background: Recently, there has been a global increase in obesity and obesity-related diseases. The prevention and treatment of obesity have become one of the most significant public health challenges worldwide in the 21st century, and how to effectively curb the occurrence of obesity has become a major global concern. Numerous studies have shown that the majority of obese individuals do not respond to leptin, and instead demonstrate leptin resistance. Clinical studies have found that acupuncture is widely used in the clinical treatment of obesity in recent years, but whether it can improve leptin resistance has not been systematically reviewed. This study is aimed to investigate the effectiveness of acupuncture in obesity with leptin resistance (LR). Methods: We searched PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Wan Fang, Technology Journal Database (VIP), and China Biology Medicine disc (CBM). Chinese Clinical Trial Registry. The time was from the establishment of the database to March 19, 2021. RevMan 5.3 software was used to assess the quality and risk of the included studies. Results: This study will be conducted in terms of clinical efficacy, serum leptin content, and body weight change. The current evidence shows that the incidence of the disease is high and the comprehensive quality is high. Conclusion: The conclusion of this review will provide a basis for judging whether acupuncture therapy is effective in the treatment of leptin resistance in obesity.

The triad of obesity, metabolic syndrome (MetS), Type 2 diabetes mellitus (T2DM) and advancing age are currently global societal problems that are expected to grow over the coming decades. This triad is associated with multiple end-organ complications of diabetic vasculopathy (maco-microvessel disease), neuropathy, retinopathy, nephropathy, cardiomyopathy, cognopathy encephalopathy and/or late-onset Alzheimer’s disease. Further, obesity, MetS, T2DM and their complications are associated with economical and individual family burdens. This review with original data focuses on the white adipose tissue-derived adipokine/hormone leptin and how its deficient signaling is associated with brain remodeling in hyperphagic, obese, or hyperglycemic female mice. Specifically, the ultrastructural remodeling of the capillary neurovascular unit, brain endothelial cells (BECs) and their endothelial glycocalyx (ecGCx), the blood-brain barrier (BBB), the ventricular ependymal cells, choroid plexus, blood-cerebrospinal fluid barrier (BCSFB), and tanycytes are examined in female mice with impaired leptin signaling from either dysfunction of the leptin receptor (DIO and db/db models) or the novel leptin deficiency (BTBR ob/ob model).

Objective — to identify in patients with Prader—Willi syndrome (PWS) hormonal disorders that lead to obesity and its progression with subsequent development of new approaches to treatment and medical social rehabilitation of such patients.Materials and methods. 24 patients aged 6—18 years were examined; 19 of them were diagnosed with deletion of chromosome 15 (del. 15 (q11—13)) with clinical manifestations of PWS. In the course of research all patients were subject to body mass index calculation, checking of glycemic level in the fasted state and throughout the day, determination of glycated hemoglobin (НbА1с, %), level of C­peptide, insulin, cortisol, prolactin, leptin, growth hormone — basal and stimulated, insulin­like growth factor­1, thyrotropin and thyroid hormones, gonadotropins (LH, FSH) and homocysteine. Results and discussion. In every patient with PWS obesity of III and IV degree was identified, 70.83 % had arterial hypertension. Insulin resistance and leptin resistance against deficiency of GH and gonadotropins and, as a consequence, hypogonadotropichypogonadism, was identified in all patients. Manifestations of hypothalamic dysfunction (neurometabolic endocrine form, 1st or 2nd clinical version) were observed in full form. However, in certain patients (2 patients aged 11 and 14 years) there was no dyslipidemia identified while in 9 patients there were no noted disorders of carbohydrate tolerance, despite all patients displaying flat glycemic curve. Hyperhomocysteinemia was identified in every patient with PWS, especially against hypothyroidism. There was an insignificant increase of cortisol and prolactin in blood against PWS, while in 70.83 % of patients was observed a transient hyperprolactinemia, which plays a key part in development and progression of obesity with complications and aggravates manifestations of hypogonadism.Conclusions. Based on analysis of hormonal and metabolic disorder values, pathogenically new approaches are proposed to the treatment of patients with PWS against psychosocial correction of pathology., Цель работы — определить гормональные нарушения у больных с синдромом Прадера—Вилли (СПВ), приводящие к ожирению и его прогрессированию, с последующей разработкой новых подходов к лечению и медико­социальной реабилитации таких больных.Материалы и методы. Обследовано 24 пациента в возрасте от 6 до 18 лет, у 19 из которых диагностированы делеции 15­й хромосомы (del. 15 (q11—13)) с клиническими проявлениями СПВ. Обследование включало определение индекса массы тела, показателей гликемии натощак и на протяжении суток, определяли гликированный гемоглобин (НbА1с, %), уровни С­пептида, инсулина, кортизола, пролактина, лептина, гормона роста — базальный и стимулированный, инсулиноподобного фактора роста­1, тиреотропина и тиреоидных гормонов, гонадотропинов (ЛГ, ФСГ) и гомоцистеина.Результаты и обсуждение. У всех пациентов с СПВ виявлено ожирение ІІІ и ІV степени, 70,83 % имели артериальную гипертензию. Инсулино­ и лептинорезистентность на фоне дефицита гормона роста и гонадотропинов и, как следствие, гипогонадотропный гипогонадизм, выявлены у всех больных. Проявления дисфункции гипоталамуса (нейроэндо­криннообменная форма, 1­й или 2­й клинический вариант) наблюдались в полном объеме, хотя у некоторых пациентов (2 пациента возрастом 11 и 14 лет) не выявлено дислипидемии и у 9 пациентов не отмечали нарушения толерантности к углеводам, хотя плоская гликемическая кривая наблюдалась у всех пациентов. Гипергомоцистеинемия выявлена у всех пациентов с СПВ, особенно при гипотиреозе. При СПВ выявлено незначительное повышение кортизола и пролактина в крови, а у 70,83 % больных наблюдалась транзиторная гіперпролактинемия, которая играет основную роль в развитии и прогрессировании ожирения с осложнениями и усиливает проявления гипогонадизма.Выводы. Анализируя показатели гормональных и метаболических нарушений предлагаются патогенетически новые подходы к лечению пациентов с СПВ на фоне психосоциальной коррекции патологии., Мета роботи — визначити гормональні порушення у хворих із синдромом Прадера—Віллі (СПВ), що призводять до ожиріння та його прогресування, з подальшою розробкою нових підходів до лікування й медико­соціальної реабілітації таких хворих.Матеріали та методи. Обстежено 24 пацієнти віком від 6 до 18 років, у 19 з яких діагностовано делеції 15­ї хромосоми (del. 15 (q11—13)) з клінічними виявами СПВ. Протягом дослідження усім хворим обчислювали індекс маси тіла, перевіряли рівень глікемії натще та протягом доби, визначали глікований гемоглобін (НbА1с, %), рівень С­пептиду, інсуліну, кортизолу, пролактину, лептину, гормона росту — базальний та стимульований, інсуліноподібного фактора росту­1, тирео­тропіну і тиреоїдних гормонів, гонадотропінів (ЛГ, ФСГ) та гомоцистеїну. Результати та обговорення. У всіх пацієнтів із СПВ виявлено ожиріння ІІІ і ІV ступеня, 70,83 % мали артеріальну гіпертензію. Інсуліно­ і лептинорезистентність на тлі дефіциту гормона росту та гонадотропінів і, як наслідок, гіпогонадотропний гіпогонадизм, виявлено у всіх хворих. Вияви дисфункції гіпоталамуса (нейроендокриннообмінна форма, 1­й або 2­й клінічний варіант) спостерігались у повному обсязі, хоча в окремих хворих (2 пацієнти віком 11 і 14 років) не виявлено дисліпідемії та у 9 пацієнтів не відмічали порушення толерантності до вуглеводів, хоча пласка глікемічна крива спостерігалась у всіх пацієнтів. Гіпергомоцистеїнемія виявлена у всіх пацієнтів із СПВ, особливо при гіпотиреозі. При СПВ виявлено незначне підвищення кортизолу і пролактину в крові, а у 70,83 % хворих спостерігалась транзиторна гіперпролактинемія, що відіграє основну роль у розвитку і прогресуванні ожиріння з ускладненнями та посилює вияви гіпогонадизму.Висновки. Аналізуючи показники гормональних і метаболічних порушень пропонуються патогенетично нові підходи до лікування хворих на СПВ на тлі психосоціальної корекції патології.

Lipids regulate a wide range of biological processes. The mechanisms by which fatty acids (FA) and its metabolites influence the hypothalamic regulation of energy homeostasis have been highly studied. However, the effect of ageing and food restriction (FR) on this process is unknown. Herein, we analyzed the gene expression, protein and phosphorylation levels of hypothalamic enzymes and transcription factors related to lipid metabolism. Experiments were performed in male Wistar rats of 3-, 8- and 24-month-old Wistar rats fed ad libitum (AL), as ageing model. Besides, 5- and 21-month-old rats were subjected to a moderate FR protocol (equivalent to ≈ 80% of normal food intake) for three months before the sacrifice. Aged Wistar rats showed a situation of chronic lipid excess as a result of an increase in de novo FA synthesis and FA levels that reach the brain, contributing likely to the development of central leptin and insulin resistance. We observe a hypothalamic downregulation of AMP-activated protein kinase (AMPK) and stearoyl-CoA desaturase (SCD1) and an increase of carnitine palmitoyltransferase-1c (CPT1c) expression.

Objective: Activation of vagal afferent neurons (VAN) by postprandial gastrointestinal signals terminates feeding and facilitates nutrient digestion and absorption. Leptin modulates responsiveness of VAN to meal-related gastrointestinal signals. Rodents with high-fat diet (HF) feeding develop leptin resistance that impairs responsiveness of VAN. We hypothesized that lack of leptin signaling in VAN reduces responses to meal-related signals, which in turn decreases absorption of nutrients and energy storage from high-fat, calorically dense food. Methods: Mice with conditional deletion of the leptin receptor from VAN (Nav1.8-Cre/LepRfl/fl; KO) were used in this study. Six-week-old male mice were fed a 45% HF for 4 weeks; metabolic phenotype, food intake, and energy expenditure were measured. Absorption and storage of nutrients were investigated in the refed state. Results: After 4 weeks of HF feeding, KO mice gained less body weight and fat mass that WT controls, but this was not due to differences in food intake or energy expenditure. KO mice had reduced expression of carbohydrate transporters and absorption of carbohydrate in the jejunum. KO mice had fewer hepatic lipid droplets and decreased expression of de novo lipogenesis-associated enzymes and lipoproteins for endogenous lipoprotein pathway in liver, suggesting decreased long-term storage of carbohydrate in KO mice. Conclusions: Impairment of leptin signaling in VAN reduces responsiveness to gastrointestinal signals, which reduces intestinal absorption of carbohydrates and de novo lipogenesis resulting in reduced long-term energy storage. This study reveals a novel role of vagal afferents to support digestion and energy storage that may contribute to the effectiveness of vagal blockade to induce weight loss.

INTRODUCTION. Obesity is a prevalent condition that accounts for significant morbidity and mortality across the globe. Despite substantial effort, most obesity pharmacotherapies have proven unsafe or ineffective. The use of obese mouse models provides unique insight into the hormones and mechanisms that regulate appetite and metabolism. Paramount among these models are the “obese” and “diabetic” mice that revealed the powerful satiety hormone leptin, revolutionizing obesity research. AREAS COVERED. In this article, we discuss work on leptin therapy, and the clinical response to leptin in humans. The authors describe the use of modern mouse genetics to study targetable mechanisms for genetic forms of human obesity. Additionally, they describe mouse models of neuromodulation and their utility in unraveling neural circuits that govern appetite and metabolism. EXPERT OPINION. Combining past and present models of obesity is required for the development of safe, effective, and impactful obesity therapy. Current research in obesity can benefit from repositories of genetically engineered mouse models to discover interactions between appetitive systems and circuits. Combining leptin therapy with other satiety signals comprising the gut-brain axis is a promising approach to induce significant enduring weight loss.

Mechanism exploitation of energy homeostasis is urgently required because of the worldwide prevailing of obesity-related metabolic disorders in human being. Although it is well known that leptin plays a central role in regulating energy balance by suppressing food intake and promoting energy expenditure, the existence of leptin resistance in majority of obese individuals hampers the utilization of leptin therapy against these disorders. However, the mechanism of leptin resistance is largely unknown in spite of the globally enormous endeavors. Current theories to interpret leptin resistance include the impairment of leptin transport, attenuation of leptin signaling, chronic inflammation, ER tress, deficiency of autophagy, as well as leptin itself. Leptin-activated leptin receptor (LepRb) signals in hypothalamus via several pathways, in which JAK2-STAT3 pathway, the most extensively investigated one, is considered to mediate the major action of leptin in energy regulation. Upon leptin stimulation the phosphorylation of STAT3 is one of the key events in JAK2-STAT3 pathway, followed by the dimerization and nuclear translocation of this molecule. Phosphorylated STAT3 (p-STAT3), as a transcription factor, binds to and regulates its target gene such as POMC gene, playing the physiological function of leptin. Regarding POMC gene in hypothalamus however little is known about the detail of its interaction with STAT3. Moreover the status of p-STAT3 and its significance in hypothalamus of DIO mice needs to be well elucidated. This review comprehends literatures on leptin and leptin resistance and especially discusses what STAT3 phosphorylation would contribute to central leptin resistance.

Archives of Allied Health Sciences, 33, 1, 19-33

Более 90% инфицированных COVID-19 проявляют легкие симптомы или не проявляют никаких симптомов, но у остальных у инфицированных случаев наблюдаются тяжелые симптомы, приводящие к значительной смертности. Возраст стал основным фактором для прогнозирования тяжести заболевания, а уровень смертности значительно выше у пожилых пациентов. Кроме того, пациенты с сопутствующими заболеваниями, такими как сахарный диабет 2 типа, сердечно-сосудистые заболевания, артериальная гипертензия и рак, имеют повышенный риск тяжелого заболевания и смерти при новой коронавирусной инфекции (COVID-19). Избыточная масса тела и ожирение стали новыми факторами риска госпитализации и увеличения смертности при COVID-19. Несколько независимых исследований показали, что люди с ожирением подвергаются большему риску тяжелого заболевания и смерти из-за COVID-19. В обзорной статье рассматриваются опубликованные данные, связанные с ожирением и избыточной массой тела, чтобы оценить возможный риск и исходы у пациентов с Covid-19 на основе их массы тела., More than 90% of those infected with COVID-19 show mild or no symptoms, but the remainder have severe symptoms, leading to significant mortality. Age has become a major factor in predicting disease severity, and mortality rates are significantly higher in older patients. In addition, patients with co-morbid conditions such as type 2 diabetes, cardiovascular disease, hypertension and cancer have an increased risk of severe illness and death from novel coronavirus infection (COVID-19). Overweight and obesity have emerged as new risk factors for hospitalization and increased mortality in COVID-19. Several independent studies have shown that obese people are at greater risk of severe illness and death due to COVID-19. The review article looks at published data related to obesity and overweight to assess the possible risk and outcomes of patients with Covid-19 based on their body weight.

1 Tabla.-- 1 Figura In obesity, an elevated accumulation and dysregulation of adipose tissue, due to an imbalance between energy intake and energy expenditure, usually coexists with the loss of responsiveness to leptin in central nervous system, and subsequently with hyperleptinemia. Leptin, a peptide hormone mainly produced by white adipose tissue, regulates energy homeostasis by stimulating energy expenditure and inhibiting food intake. Human obesity is characterized by increased plasma leptin levels, which have been related with different obesity-associated complications, such as chronic inflammatory state (risk factor for diabetes, cardiovascular and autoimmune diseases), as well as infertility and different types of cancer. Besides, leptin is also produced by placenta, and high leptin levels during pregnancy may be related with some pathological conditions such as gestational diabetes. This review focuses on the current insights and emerging concepts on potentially valuable nutrients and food components that may modulate leptin metabolism. Notably, several dietary food components, such as phenols, peptides, and vitamins, are able to decrease inflammation and improve leptin sensitivity by up- or down-regulation of leptin signaling molecules. On the other hand, some food components, such as saturated fatty acids may worsen chronic inflammation increasing the risk for pathological complications. Future research into nutritional mechanisms that restore leptin metabolism and signals of energy homeostasis may inspire new treatment options for obesity-related disorders. The present work was funded by grants from the Instituto de Salud Carlos III (ISCIII), PS12/00117, and PI15/01535, PI19/01741 funded in part by FEDER Funds, to Víctor Sánchez-Margalet.

Obesity, an epidemiological disorder, is related to various complications in both the developed and developing world. It epitomizes a crucial risk factor for health, decreasing productivity and life expectancy while increasing health care costs worldwide. Conventional therapies with synthetic drugs or bariatric surgery, associated with numerous side effects, recurrence, and surgical complexity, have been restricted in their use. Lifestyle changes and dietary restrictions are the proven methods for successful weight loss, although maintaining a strict lifestyle is a challenge. Multiple natural products have been explored for weight management with varied efficacy. The current review explores less explored natural herbs, their active constituents, and their mechanisms of action against obesity.

Therapeutic peptides derived proteins with alpha-reconformation states like antibody shape have shown potential effects in combating terrible diseases linked with earlier signs of angiogensis, mutagenesis and transgenesis. Alpha reconformation in material design refers to the folding of the peptide chains and their transitions under reversible chemical bonds of disulfide chemical bridges and further non-covalence lesions. Thus, the rational design of signal peptides into alpha-helix is intended in increasing the defending effects of peptides into cores like adjuvant antibiotic and/or vaccines. Thereby, the signal peptides are able in displaying multiple eradicating regions by changing crystal-depositions and deviation angles. These types of molecular structures could have multiple advantages in tracing disease syndromes and impurities by increasing the host defense against the fates of pathogens and viruses, eventually leading to the loss in signaling by increasing peptide susceptibility levels to folding and unfolding and therefore, formation of transgenic peptide models. Alpha reconformation peptides is aimed in triggering as well as other regulatory functions such as remodulating metabolic chain disorders of lipolysis and glucolysis by increasing the insulin and leptin resistance for best lipid storages and lipoprotein density distributions.

Rats consuming 30% sucrose solution and a sucrose-free diet (LiqS) become leptin resistant, whereas rats consuming sucrose from a formulated diet (HS) remain leptin responsive. This study tested whether leptin resistance in LiqS rats extended beyond a failure to inhibit food intake and examined leptin responsiveness in the hypothalamus and hindbrain of rats offered HS, LiqS, or a sucrose-free diet (NS). Female LiqS Sprague-Dawley rats initially only partially compensated for the calories consumed as sucrose, but energy intake matched that of HS and NS rats when they were transferred to calorimetry cages. There was no effect of diet on energy expenditure, intrascapular brown fat tissue (IBAT) temperature, or fat pad weight. A peripheral injection of 2 mg of leptin/kg on day 23 or day 26 inhibited energy intake of HS and NS but not LiqS rats. Inhibition occurred earlier in HS rats than in NS rats and was associated with a smaller meal size. Leptin had no effect on energy expenditure but caused a transient rise in IBAT temperature of HS rats. Leptin increased the phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) in the hindbrain and ventromedial hypothalamus of all rats. There was a minimal effect of leptin in the arcuate nucleus, and only the dorsomedial hypothalamus showed a correlation between pSTAT3 and leptin responsiveness. These data suggest that the primary response to leptin is inhibition of food intake and the pattern of sucrose consumption, rather than calories consumed as sucrose, causes leptin resistance associated with site-specific differences in hypothalamic leptin signaling.

International audience; Objectives: Pediatric obesity and sleep-disordered breathing (SDB) are strongly associated, and both promote metabolic impairments. However, the effects of a lifestyle intervention on the overall metabolic syndrome (MetS) are unknown. The objectives were i) to evaluate the effects of a lifestyle intervention on cardiometabolic risk (CMR), assessed with a dichotomous (MetS) and a continuous (MetScoreFM) instrument, in obese adolescents with and without SDB and ii) to compare the post-intervention cardiometabolic responses between adolescents with persistent (apnea-hypopnea index; AHI≥2) or normalized-SDB (AHI

When the human body has stored enough energy from food, it releases a hormone called leptin that travels to the brain and stops feelings of hunger. This hormone moves through the bloodstream and can affect other organs, such as the liver, which also help control our body’s energy levels. Most people with obesity have very high levels of leptin in their blood, but are resistant to its effects and will therefore continue to feel hungry despite having stored enough energy. One of the proteins that controls the levels of leptin is a receptor called sOb-R, which is released by the liver and binds to leptin as it travels in the blood. Individuals with high levels of this receptor often have less free leptin in their bloodstream and a lower body weight. Another protein that helps the body to regulate its energy levels is the cannabinoid-1 receptor, or CB1R for short. In people with obesity, this receptor is overactive and has been shown to contribute to leptin resistance, which is when the brain becomes less receptive to leptin. Previous work in mice showed that blocking CB1R reduced the levels of leptin and allowed mice to react to this hormone normally again, but it remained unclear whether CB1R affects how other organs, such as the liver, respond to leptin. To answer this question, Drori et al. blocked the CB1R receptor in the liver of mice eating a high-fat diet, either by using a drug or by deleting the gene that codes for this protein. This caused mice to have higher levels of sOb-R circulating in their bloodstream. Further experiments showed that this change in sOb-R was caused by the levels of a protein called CHOP increasing in the liver when CB1R was blocked. Drori et al. found that inhibiting CB1R caused these obese mice to lose weight and have healthier, less fatty livers as a result of their livers no longer being resistant to the effects of leptin. Scientists, doctors and pharmaceutical companies are trying to develop new strategies to combat obesity. The results from these experiments suggest that blocking CB1R in the liver could allow this organ to react to leptin appropriately again. Drugs blocking CB1R, including the one used in this study, will be tested in clinical trials and could provide a new approach for treating obesity.

Background Obstructive sleep apnea (OSA) syndrome is strongly associated with obesity and inflammation. Adipose tissue is not simply an inactive storage depot for lipids but is also an active endocrine organ that plays a crucial role regarding endocrine, metabolic, and inflammatory signals of which leptin, ghrelin, adiponectin, and resistin play an important role in body homeostasis. So, we aimed to study leptin and ghrelin serum levels in OSA patients. Patients and methods The study included 15 healthy control participants and 30 patients diagnosed with OSA. All patients were subjected to history taking, clinical examination, routine laboratory investigations, and polysomnography. Manual analysis and scoring were performed using the criteria established by the American Academy of Sleep Medicine. Results Patient’s serum leptin ranged between 11.4 and 66.4 ng/ml with a mean±SD of 33.303±15.728 while in control participants it ranged between 0.5 and 34.7 ng/ml with a mean±SD of 10.467±10.339. Patient’s serum ghrelin ranged between 103.5 and 6673 pg/ml with a mean±SD of2034.527±1815.687 while in control participants it ranged between 976 and 2184 pg/ml with a mean±SD of 1682.467±334.064. Leptin levels were statistically significantly higher in obstructive sleep apnea syndrome (OSAH) patients versus control participants. Leptin levels statistically significantly correlated with some indices of obesity hypoventilation syndrome severity, that is, apnea–hypopnea index and desaturation index. Leptin levels statistically significantly correlated with a variety of anthropometric measurements, including BMI and neck circumference. Leptin levels statistically significantly correlated with serum triglyceride levels. Regression analysis showed that the best predicting variables for leptin levels were the lowest oxygen saturation, average SaO2, sleep time with oxygen saturation of less than 90% (t90%) and BMI. There was no statistically significant difference between the two studied groups regarding serum ghrelin levels and no statistically significant correlation was found between serum ghrelin and any parameter.

Prolonged obesity causes “selective leptin resistance” (SLR), in which cardiovascular responses to leptin are intact but metabolic responses are lost. High fat diet (HFD) for 10 weeks causes SLR in C57BL/6J mice, as it attenuates metabolic (adipose) sympathetic nervous activity (SNA) responses to leptin but has no effect on cardiovascular SNA responses. Using single-nucleus RNAsequencing, we recently discovered disruption of leptin and CREB signaling specifically in Agouti-related peptide ( Agrp ) neurons of the arcuate nucleus of the hypothalamus (ARC) after 10-week HFD. Because C57BL/6J mice are generally resistant to diet-induced changes in blood pressure (BP), one goal of this study was to examine BP in this model. Further, we sought to examine effects of prolonged HFD on CREB signaling and Agrp mRNA within the ARC. Male C57BL/6J mice were maintained on chow (2920x) or HFD (D12451) from 8-18 weeks of age. Intake behaviors were studied in metabolic cages and bomb calorimetry; body composition via nuclear magnetic resonance; BP and HR via radiotelemetry; and cardiac function via echocardiography. ARC biopsies were analyzed for Agrp mRNA via qPCR and for CREB and ERK proteins using capillary electrophoresis-based Western. HFD increased caloric uptake, leading to increases in body and fat mass (pAgrp mRNA in the ARC. We conclude that prolonged HFD increases cardiovascular SNA in C57BL/6J mice without effect on BP because of cardiac compensation. Further, this model causes SLR at the level of the ARC Agrp neuron, in a mechanism likely involving alterations in CREB- and ERK-mediated signaling.

The peptide hormone leptin regulates food intake, body mass, and reproductive function and plays a role in fetal growth, proinflammatory immune responses, angiogenesis and lipolysis. Leptin is a product of the obese (ob) gene and, following synthesis and secretion from fat cells in white adipose tissue, binds to and activates its cognate receptor, the leptin receptor (LEP-R). LEP-R distribution facilitates leptin’s pleiotropic effects, playing a crucial role in regulating body mass via a negative feedback mechanism between adipose tissue and the hypothalamus. Leptin resistance is characterized by reduced satiety, over-consumption of nutrients, and increased total body mass. Often this leads to obesity, which reduces the effectiveness of using exogenous leptin as a therapeutic agent. Thus, combining leptin therapies with leptin sensitizers may help overcome such resistance and, consequently, obesity. This review examines recent data obtained from human and animal studies related to leptin, its role in obesity, and its usefulness in obesity treatment.

The soluble isoform of leptin receptor (sOb-R), secreted by the liver, regulates leptin bioavailability and bioactivity. Its reduced levels in diet-induced obesity (DIO) contribute to hyperleptinemia and leptin resistance, effects that are regulated by the endocannabinoid (eCB)/CB1R system. Here we show that pharmacological activation/blockade and genetic overexpression/deletion of hepatic CB1R modulates sOb-R levels and hepatic leptin resistance. Interestingly, peripheral CB1R blockade failed to reverse DIO-induced reduction of sOb-R levels, increased fat mass and dyslipidemia, and hepatic steatosis in mice lacking C/EBP homologous protein (CHOP), whereas direct activation of CB1R in wild-type hepatocytes reduced sOb-R levels in a CHOP-dependent manner. Moreover, CHOP stimulation increased sOb-R expression and release via a direct regulation of its promoter, while CHOP deletion reduced leptin sensitivity. Our findings highlight a novel molecular aspect by which the hepatic eCB/CB1R system is involved in the development of hepatic leptin resistance and in the regulation of sOb-R levels via CHOP., eLife digest When the human body has stored enough energy from food, it releases a hormone called leptin that travels to the brain and stops feelings of hunger. This hormone moves through the bloodstream and can affect other organs, such as the liver, which also help control our body’s energy levels. Most people with obesity have very high levels of leptin in their blood, but are resistant to its effects and will therefore continue to feel hungry despite having stored enough energy. One of the proteins that controls the levels of leptin is a receptor called sOb-R, which is released by the liver and binds to leptin as it travels in the blood. Individuals with high levels of this receptor often have less free leptin in their bloodstream and a lower body weight. Another protein that helps the body to regulate its energy levels is the cannabinoid-1 receptor, or CB1R for short. In people with obesity, this receptor is overactive and has been shown to contribute to leptin resistance, which is when the brain becomes less receptive to leptin. Previous work in mice showed that blocking CB1R reduced the levels of leptin and allowed mice to react to this hormone normally again, but it remained unclear whether CB1R affects how other organs, such as the liver, respond to leptin. To answer this question, Drori et al. blocked the CB1R receptor in the liver of mice eating a high-fat diet, either by using a drug or by deleting the gene that codes for this protein. This caused mice to have higher levels of sOb-R circulating in their bloodstream. Further experiments showed that this change in sOb-R was caused by the levels of a protein called CHOP increasing in the liver when CB1R was blocked. Drori et al. found that inhibiting CB1R caused these obese mice to lose weight and have healthier, less fatty livers as a result of their livers no longer being resistant to the effects of leptin. Scientists, doctors and pharmaceutical companies are trying to develop new strategies to combat obesity. The results from these experiments suggest that blocking CB1R in the liver could allow this organ to react to leptin appropriately again. Drugs blocking CB1R, including the one used in this study, will be tested in clinical trials and could provide a new approach for treating obesity.

Obesity is closely associated with various metabolic disorders, including leptin resistance, which is characterized by high circulating leptin levels. Probiotics can decrease circulating leptin levels by alteration of the gut microbiota. Thus, they may have anti-obesogenic effects. In this study, the effects of administration of a probiotic bacterium, Lactobacillus rhamnosus GG (LGG), on gut microbiota and modulation of leptin resistance were evaluated in mice. Male Balb/C mice aged 7 weeks were fed either a normal diet (ND), high-fat diet (HFD), HFD supplemented with low-dose LGG (108 CFU/mouse/day), or HFD supplemented with high-dose LGG (1010 CFU/mouse/day) for 10 weeks. Significantly increased body weight, epididymal fat weight, and decreased leptin responsiveness to exogenous leptin treatment and ratio of villus height to crypt depth were observed in the HFD-fed mice compared to the ND-fed mice. Moreover, a remarkable increase in the proportion of Proteobacteria and ratio of Firmicutes/Bacteroidetes in the fecal microbiota were also observed in the HFD-fed mice. Supplementation of HFD with high-dose LGG restored exogenous leptin responsiveness, increased the ratio of villus height to crypt depth, and decreased the proportion of Proteobacteria in fecal microbiota. These findings suggest that LGG supplementation might alleviate leptin resistance caused by an HFD through the improvement of the digestive health of the host.

Background A growing body of evidence shows that hypothalamic inflammation is an important factor in the initiation of obesity. In particular, reactive gliosis accompanied by inflammatory responses in the hypothalamus are pivotal cellular events that elicit metabolic abnormalities. In this study, we examined whether MyD88 signaling in hypothalamic astrocytes controls reactive gliosis and inflammatory responses, thereby contributing to the pathogenesis of obesity. Methods To analyze the role of astrocyte MyD88 in obesity pathogenesis, we used astrocyte-specific Myd88 knockout (KO) mice fed a high-fat diet (HFD) for 16 weeks or injected with saturated free fatty acids. Astrocyte-specific gene expression in the hypothalamus was determined using real-time PCR with mRNA purified by the Ribo-Tag system. Immunohistochemistry was used to detect the expression of glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, phosphorylated signal transducer and activator of transcription 3, and α-melanocyte-stimulating hormone in the hypothalamus. Animals’ energy expenditure was measured using an indirect calorimetry system. Results The astrocyte-specific Myd88 KO mice displayed ameliorated hypothalamic reactive gliosis and inflammation induced by injections of saturated free fatty acids and a long-term HFD. Accordingly, the KO mice were resistant to long-term HFD-induced obesity and showed an improvement in HFD-induced leptin resistance. Conclusions These results suggest that MyD88 in hypothalamic astrocytes is a critical molecular unit for obesity pathogenesis that acts by mediating HFD signals for reactive gliosis and inflammation.

The adipocyte-derived adipokine leptin exerts pleiotropic effects, which are essential for the regulation of energy balance and cell metabolism, for controlling inflammatory and immune responses, and for the maintenance of homeostasis of the cardiovascular system. Leptin resistance in obese or type 2 diabetes mellitus (T2DM) patients is defined as a decrease in tissue response to leptin. In the cardiovascular system, leptin resistance exhibits the adverse effect on the heart's response to stress conditions and promoting cardiac remodeling due to impaired cardiac metabolism, increased fibrosis, vascular dysfunction, and enhanced inflammation. Leptin resistance or leptin signaling deficiency results in the risk increase of cardiac dysfunction and heart failure, which is a leading cause of obesity- and T2DM-related morbidity and mortality. Animal studies using leptin- and leptin receptor- (Lepr) deficient rodents have provided many useful insights into the underlying molecular and pathophysiological mechanisms of obese- and T2DM-associated metabolic and cardiovascular diseases. However, none of the animal models used so far can fully recapitulate the phenotypes of patients with obese or T2DM. Therefore, the role of leptin in the human cardiovascular system, and whether leptin affects cardiac function directly or acts through a leptin-regulated neurohumoral pathway, remain elusive. As the prevalence of obesity and diabetes is continuously increasing, strategies are needed to develop and apply human cell-based models to better understand the precise role of leptin directly in different cardiac cell types and to overcome the existing translational barriers. The purpose of this review is to discuss the mechanisms associated with leptin signaling deficiency or leptin resistance in the development of metabolic and cardiovascular diseases. We analyzed and comprehensively addressed substantial findings in pathophysiological mechanisms in commonly used leptin- or Lepr-deficient rodent models and highlighted the differences between rodents and humans. This may open up new strategies to develop directly and reliably applicable models, which resemble the human pathophysiology in order to advance health care management of obesity- and T2DM-related cardiovascular complications.

Leptin has a modulatory impact on the course of inflammation, affecting the expression of proinflammatory cytokines and their receptors. Pathophysiological leptin resistance identified in humans occurs typically in sheep during the long-day photoperiod. This study aimed to determine the effect of the photoperiod with relation to the leptin-modulating action on the expression of the proinflammatory cytokines and their receptors in the anterior pituitary under physiological or acute inflammation. Two in vivo experiments were conducted on 24 blackface sheep per experiment in different photoperiods. The real-time PCR analysis for the expression of the genes IL1B, IL1R1, IL1R2, IL6, IL6R, IL6ST, TNF, TNFR1, and TNFR2 was performed. Expression of all examined genes, except IL1&beta, and IL1R2, was higher during short days. The leptin injection increased the expression of all examined genes during short days. In short days the synergistic effect of lipopolysaccharide and leptin increased the expression of IL1B, IL1R1, IL1R2, IL6, TNF, and TNFR2, and decreased expression of IL6ST. This mechanism was inhibited during long days for the expression of IL1R1, IL6, IL6ST, and TNFR1. The obtained results suggest the occurrence of leptin resistance during long days and suggest that leptin modulates the course of inflammation in a photoperiod-dependent manner in the anterior pituitary.

Leptin and its receptors have been identified as key regulators of body weight and energy homeostasis. A decrease in tissue sensitivity to leptin leads to the development of obesity and metabolic disorders, such as insulin resistance and dyslipidemia. Mechanisms underlying the development of leptin resistance include mutations in the genes encoding leptin and its receptors, as well as proteins involved in self-regulation of leptin synthesis and blood-brain barrier permeability. Leptin resistance encompasses a complex pathophysiological phenomenon with a number of potential research lines. In this review, we analyze the existing data on the methods used to diagnose leptin resistance.

Olga Gruzdeva,1,2 Daria Borodkina,3 Evgenya Uchasova,1 Yulia Dyleva,1 Olga Barbarash1,2 1Federal State Budgetary Institution, Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russian Federation; 2Federal State Budget Educational Institution of Higher Education, Kemerovo State Medical University of the Ministry of Healthcare of the Russian Federation, Kemerovo, Russian Federation; 3Autonomous Public Healthcare Institution of the Kemrovo Region, Kemerovo Regional Clinical Hospital Named After S.V. Beliyaev, Regional Center for Diabetes, Kemerovo, Russian Federation Abstract: Leptin and its receptors have been identified as key regulators of body weight and energy homeostasis. A decrease in tissue sensitivity to leptin leads to the development of obesity and metabolic disorders, such as insulin resistance and dyslipidemia. Mechanisms underlying the development of leptin resistance include mutations in the genes encoding leptin and its receptors, as well as proteins involved in self-regulation of leptin synthesis and blood–brain barrier permeability. Leptin resistance encompasses a complex pathophysiological phenomenon with a number of potential research lines. In this review, we analyze the existing data on the methods used to diagnose leptin resistance. Keywords: leptin, leptin resistance, soluble leptin receptor