Leptin Sensitivity Research Articles

Is "Leptin Resistance" Another Key Resistance to Manage Type 2 Diabetes?

Although novel pharmacological options for the treatment of type 2 diabetes mellitus (DM2) have been observed to modulate the functionality of several key organs in glucose homeostasis, successful regulation of insulin resistance (IR), body weight management, and pharmacological treatment of obesity remain notable problems in endocrinology. Leptin may be a pivotal player in this scenario, as an adipokine which centrally regulates appetite and energy balance. In obesity, excessive caloric intake promotes a low-grade inflammatory response, which leads to dysregulations in lipid storage and adipokine secretion. In turn, these entail alterations in leptin sensitivity, leptin transport across the blood-brain barrier and defects in post-receptor signaling. Furthermore, hypothalamic inflammation and endoplasmic reticulum stress may increase the expression of molecules which may disrupt leptin signaling. Abundant evidence has linked obesity and leptin resistance, which may precede or occur simultaneously to IR and DM2. Thus, leptin sensitivity may be a potential early therapeutic target that demands further preclinical and clinical research. Modulators of insulin sensitivity have been tested in animal models and small clinical trials with promising results, especially in combination with agents such as amylin and GLP-1 analogs, in particular, due to their central activity in the hypothalamus.

DHA reduces hypothalamic inflammation and improves central leptin signaling in mice

AimsAnti-obesity effects and improved leptin sensitivity from n-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported in diet-induced obese animals. This study sought to determine the beneficial central effects and mechanism of docosahexaenoic acid (DHA, 22:6 n-3) in high-fat (HF) diet fed mice. Main methodsMale C57BL/6J mice were given HF diet with or without intracerebroventricular (icv) injection of docosahexaenoic acid (DHA, 22:6 n-3) for two days. Central leptin sensitivity, hypothalamic inflammation, leptin signaling molecules and tyrosine hydroxylase (TH) were examined by central leptin sensitivity test and Western blot. Furthermore, the expression of hepatic genes involved in lipid metabolism was examined by RT-PCR. Key findingsWe found that icv administration of DHA not only reduced energy intake and body weight gain but also corrected the HF diet-induced hypothalamic inflammation. DHA decreased leptin signaling inhibitor SOCS3 and improved the leptin JAK2-Akt signaling pathways in the hypothalamus. Furthermore, icv administration of DHA improved the effects of leptin in the regulation of mRNA expression of enzymes related to lipogenesis, fatty acid β-oxidation, and cholesterol synthesis in the liver. DHA increased leptin-induced activation of TH in the hypothalamus. SignificanceTherefore, increasing central DHA concentration may prevent the deficit of hypothalamic regulation, which is associated with disorders of energy homeostasis in the liver as a result of a high-fat diet.

Serum Leptin Versus C-Reactive Protein in The Early Diagnosis of Neonatal Sepsis

Background: Neonatal sepsis is a systemic inflammatory reaction that is triggered by an infective agent. When sepsis occurs, multiple redundant inflammatory cytokines are released into the blood stream, including, leptin, Creactive protein (CRP). Aim of the Study: was to compare the sensitivity of serum leptin and C-reactive protein in early diagnosis of neonatal sepsis. Patients and Methods: This was a prospective cohort study conducted in the Zagazig General Hospital and included (34) newborn infants. The tests used were, blood culture, C - Reactive protein Level, and serum leptin level. Results: 76.5% of the studied group had +ve culture results. The most frequent organism was staph 12 (35.3%). There was a statistically significant increase in CRP and Leptin among +ve cases compared to –ve cases. There was a positive statistically significant correlation between serum leptin levels and CRP. The sensitivity of CRP in the diagnosis of sepsis at the cut off 18 was 65.4%, specificity was 50% and the accuracy was 61.8%. While the sensitivity of Leptin in the diagnosis of sepsis at the cut off 0.07 was 84.6%, specificity was 87.5% and the accuracy was 85.3%. Conclusion: Leptin is an effective diagnostic marker for sepsis and more accurate when compared with CRP

Inhibition of Plasminogen Activator Inhibitor-1 Activation Suppresses High Fat Diet-Induced Weight Gain via Alleviation of Hypothalamic Leptin Resistance.

Leptin resistance is an important mechanism underlying the development and maintenance of obesity and is thus regarded as a promising target of obesity treatment. Plasminogen activator inhibitor 1 (PAI-1), a physiological inhibitor of tissue-type and urokinase-type plasminogen activators, is produced at high levels in adipose tissue, especially in states of obesity, and is considered to primarily be involved in thrombosis. PAI-1 may also have roles in inter-organ tissue communications regulating body weight, because PAI-1 knockout mice reportedly exhibit resistance to high fat diet (HFD)-induced obesity. However, the role of PAI-1 in body weight regulation and the underlying mechanisms have not been fully elucidated. We herein studied how PAI-1 affects systemic energy metabolism. We examined body weight and food intake of PAI-1 knockout mice fed normal chow or HFD. We also examined the effects of pharmacological inhibition of PAI-1 activity by a small molecular weight compound, TM5441, on body weight, leptin sensitivities, and expressions of thermogenesis-related genes in brown adipose tissue (BAT) of HFD-fed wild type (WT) mice. Neither body weight gain nor food intake was reduced in PAI-1 KO mice under chow fed conditions. On the other hand, under HFD feeding conditions, food intake was decreased in PAI-1 KO as compared with WT mice (HFD-WT mice 3.98 ± 0.08 g/day vs HFD-KO mice 3.73 ± 0.07 g/day, P = 0.021), leading to an eventual significant suppression of weight gain (HFD-WT mice 40.3 ± 1.68 g vs HFD-KO mice 34.6 ± 1.84 g, P = 0.039). Additionally, TM5441 treatment of WT mice pre-fed the HFD resulted in a marked suppression of body weight gain in a PAI-1-dependent manner (HFD-WT-Control mice 37.6 ± 1.07 g vs HFD-WT-TM5441 mice 33.8 ± 0.97 g, P = 0.017). TM5441 treatment alleviated HFD-induced systemic and hypothalamic leptin resistance, before suppression of weight gain was evident. Moreover, improved leptin sensitivity in response to TM5441 treatment was accompanied by increased expressions of thermogenesis-related genes such as uncoupling protein 1 in BAT (HFD-WT-Control mice 1.00 ± 0.07 vs HFD-WT-TM5441 mice 1.32 ± 0.05, P = 0.002). These results suggest that PAI-1 plays a causative role in body weight gain under HFD-fed conditions by inducing hypothalamic leptin resistance. Furthermore, they indicate that pharmacological inhibition of PAI-1 activity is a potential strategy for alleviating diet-induced leptin resistance in obese subjects.

The Impact of Photoperiod on the Leptin Sensitivity and Course of Inflammation in the Anterior Pituitary.

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 IL1β 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.

241-LB: Positive Regulation of JAK/STAT at Signaling with SOCS3-Derived Cell-Permeable Binding Domain to ObR Induces Anti-obesity Effect

Aim: Leptin, a hormone which regulates food intake and energy expenditure, is excessively expressed in obese patients. Leptin signaling is regulated by a negative feedback regulator, suppressor of cytokine signaling 3 (SOCS3) that competitively binds to the leptin receptor (ObR) and promotes leptin resistance. We hypothesized that an exogenously delivered SOCS3 binding domain (SH2) would compete with SOCS3 for binding to p-Tyr985ObR, and thereby maintain leptin-initiated JAK/STAT signaling. Method: Cell-permeable, dominant-interfering ΔSOCS3 protein consists of the SOCS3 SH2 domain, a sequence optimized-advanced macromolecule transduction domain to deliver the protein into cells and tissues to facilitate soluble purification, biologically active proteins. Intracellular delivery of ΔSOCS3 was tested for the ability to enhance leptin signaling and sensitivity in diet-induced obese (DIO) mice. Result: The cell-permeable ΔSOCS3 was delivered efficiently into cell types and tissues examined including the hypothalamus; thus, the protein appeared to cross the blood-brain barrier. CP-ΔSOCS3 competitively bound p-Tyr985ObR and blocked negative regulation by endogenous SOCS3 as assessed by increased levels of phospho-STAT3. DIO mice treated with CP-ΔSOCS3 showed 12.1% body weight loss in 14 days. In addition, fat volume (53.5%), food intake (29.2%), serum leptin (93.1%) and expression of SOCS3 mRNA were also decreased in CP-ΔSOCS3-treated compared to mice treated with diluent. In addition, treatment group showed a significant increase in STAT3 phosphorylation and pro-opiomelanocortin in the hypothalamus. Conclusion: CP-ΔSOCS3 appeared to competitively suppress feedback inhibition of JAK/STAT signaling by endogenous SOCS3 thereby enhancing leptin sensitivity. This establishes the importance of SOCS3 in the biology of leptin signaling and resistance and suggests CP-ΔSOCS3 might be used as a mechanism-specific weight-loss therapy. Disclosure K. Lee: None. J. Jeon: None. S. Kim: None. H. Kang: None. J. Kwak: None. Y. Choi: None. D. Jo: None.

1720-P: The Modulation in Glucose Metabolism by B1 Kinin Receptor Does Not Depend in Hepatic Insulin Signaling

Background: The kinin B1 receptor (B1R), an inducible effector of Kallikrein-Kinin System during inflammation, has been blamed also to influence glucose metabolism and leptin sensitivity. Aim: To investigate the effects of cafeteria diet (CAF) on hepatic glucose metabolism in B1R knockout mice (B1RKO). Methods: Two months old male C57Bl/6 wild type and B1RKO mice were fed with standard chow (SC) or CAF ad libitumfor 14 weeks (WT-SC n=7; B1RKO-SC n=8; WT-CAF n=7; B1RKO-CAF n =10). We performed glucose tolerance test (GTT) and insulin tolerance test (ITT) at the last week before organs collection. HOMA IR index was calculated. Quantitative PCR was used to determine hepatic expression of glucose-6-phospatase (G6Pase), glucokinase (GK), phosphoenolpyruvate carboxykinase (PEPCK), fructose 1,6-bisphosphatase (FBPase1) and hepatocyte nuclear factor 4 alpha (HNF4A). We also performed western blot to analyze AKT phosphorylation in liver. Two-way ANOVA was used to analyze differences between groups. Values were expressed as mean ± SEM and p ≤0.05 was considered statistically significant. Results: Although the increment of glucose area under the curve during GTT was lower in B1RKO-CAF than WT-CAF (WT-SC 46.246 ± 4.302 vs. B1RKO-SC 35.699 ± 3.383; p=0.03; and B1RKO-CAF 28.521 ± 5.338 vs. WT-CAF 56.564 ± 3.477; AUC p=0.0001), B1RKO mice presented a similar decay in glucose levels during ITT as well as HOMA-IR values . While there was a decrease in liver mRNA expression of G6Pase and PEPCK, GK expression increased in mice fed with CAF diet, without differences between genotypes. FBPase1 and HNF4A mRNA expression were not different between groups. Liver AKT phosphorylation increased with CAF in both C57Bl/6 wild type and B1RKO mice. Conclusion: The increased glucose uptake of B1RKO mice during GTT might not be related to insulin signaling in the liver, since no changes were observed in insulin resistance or in the hepatic expression of gluconeogenesis regulatory enzymes. Disclosure P. Espíndola Correia: None. C.B. Gomes: None. P.N. Merello: None. G.R. Natividade: None. C.C. Barros: None. F. Gerchman: None. Funding Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (16-0397)

211-OR: Hypothalamic Slug Couples Overnutrition States to Epigenetic Reprogramming of Leptin Neural Circuits, Obesity, and Type 2 Diabetes

Leptin protects against obesity and metabolic disease mainly through leptin neural circuits in the hypothalamus. Leptin binds to and activates hypothalamic leptin receptors (LepR), thereby suppressing food intake and increasing energy expenditure. Counterintuitively, obesity is associated with hyperleptinemia in rodents and humans. Moreover, leptin therapies fail to ameliorate obesity in humans. These observations support a notion that obese subjects develop leptin resistance. Multiple positive and negative regulators of LepR signaling have been identified to influence leptin sensitivity, including Sh2b1, SOCS3, and PTP1b. However, factors, which couple overnutrition states to leptin resistance, are not fully understood. Here, we observed that high fat diet (HFD) feeding markedly upregulates Slug, a nuclear epigenetic regulator, in the hypothalamus. Remarkably, LepR neuron-specific deletion of Slug (SlugΔLepR) reversed HFD-induced hyperleptinemia, energy imbalance, obesity, insulin resistance, glucose intolerance, and liver steatosis. Conversely, overexpression of Slug (MBHSlug) but not an epigenetic-defective Slug mutant in the mediobasal hypothalamus resulted in obesity, insulin resistance, glucose intolerance, and fatty liver disease in mice. We found that Slug physically binds to the LepR promoter and suppresses LepR promoter activity; accordingly, hypothalamic LepR expression was high in SlugΔLepR mice and low in MBHSlug mice. Furthermore, Slug increased the levels of LepR promoter H3K27 methylation, a repressive epigenetic mark, in the hypothalamus, presumably by recruiting H3K37 methytransferase Ezh2 to the LepR promoter. Indeed, Ezh2 inhibitor treatment blocked Slug suppression of LepR promoter activity. Collectively, we unravel a previously unrecognized Slug-elicited epigenetic reprograming of LepR pathways that couple overnutrition states to leptin resistance, obesity, and metabolic disease. Disclosure M. Kim: None. L. Jiang: None. M.G. Myers: Research Support; Self; AstraZeneca, Novo Nordisk Inc. L. Rui: None. Funding National Institutes of Health (F32DK120111)

Selenium Regulates Hypothalamic Control of Energy Metabolism in a Sexually Dimorphic Manner

Abstract Objectives The trace element selenium (Se) is known mainly for its antioxidant properties and is critical for proper brain function. The role of Se in regulating energy metabolism, and the sexually dimorphic nature of Se functions, however, are underappreciated, and warrant increased attention. Recent work in our lab has highlighted the importance of Se utilization in hypothalamic regulation of energy metabolism. Dietary Se is incorporated into selenoproteins in the form of the unique amino acid selenocysteine (Sec). The objective of this study was to assess the role of selenoproteins in Agouti-related peptide (Agrp)-positive neurons, an orexigenic sub-population of the hypothalamus. Methods We generated mice with Agrp-Cre-driven deletion of selenocysteine tRNA (Trsp-Agrp KO mice), which is essential for Sec incorporation into selenoproteins, thus ablating selenoprotein synthesis in Agrp-positive neurons. The metabolic phenotype of Trsp-Agrp KO mice challenged with a high-fat diet was characterized via glucose tolerance test (i.p. injection) and the use of analytical chambers to measure food intake and respiratory metabolism. Prior to sacrifice, mice were challenged with leptin (i.p. injection) to assess neuronal leptin responsivity via immunohistochemistry and western blot. Brown adipose tissue (BAT) morphology and thermogenic protein expression were also analyzed. Results Female Trsp-Agrp KO mice displayed resistance to diet-induced obesity, which was accompanied by improved glucose tolerance and elevated energy expenditure levels without changes in food intake. Female Trsp-Agrp KO mice also had greater leptin sensitivity and showed signs of elevated BAT thermogenesis. Male Trsp-Agrp KO mice displayed no changes in metabolic phenotype. Conclusions Loss of selenoproteins in Agrp-positive neurons of the hypothalamus promotes energy expenditure and reduces diet-induced obesity in a sexually dimorphic manner, leading to resistance to a high-fat diet in females. Funding Sources This work was funded by grant support from the National Institute of Diabetes and Digestive and Kidney Diseases (MJB) and Ola HAWAII, a grant from the National Institute on Minority Health and Health Disparities.

SAT-028 Leptin, Leptin Soluble Receptor and FLI in Healthy and Preeclamptic Pregnancies

ContextLeptin is an adipokine involved in many pleiotropic and key physiological actions and circulates free and active, or inactive bound to the leptin binding protein and sOB-r. Thus, the ratio Leptin/sOB-r or free leptin index (FLI) is commonly used as a marker of leptin sensitivity in different pathologies.ObjectiveEvaluate serum concentrations of leptin and sOB-r and determine FLI in healthy pregnant and mild pre – eclamptic women in the three trimesters of gestation.DesignA nested case-control study within a prospective cohort study of pregnant women, enrolled in the Department of Obstetrics and Gynecology of the School of Medicine at Universidad Nacional.Main Outcome Measure and MethodsFrom the initial cohort, 46 healthy pregnant women and 19 mild pre – eclamptic pregnant women were randomly selected. Anthropometric, biochemical and clinical parameters were determined during three stages of pregnancy [1st (11.3±2.3 weeks), 2nd (24.4±3.10 weeks) and 3rd (34.84±4.41 weeks) periods of gestation]. Data were presented as mean ± SD. A p value <0.05 was considered to be statistically significant.ResultsSerum leptin levels and sOB-r levels rose significantly throughout pregnancy in both healthy women [Leptin (1st 23.28±9.87 ng/mL; 2nd 34.58±18.45 ng/mL; 3rd 38.27±19.64 ng/mL trimester) (p=0.0001); sOB-r (1st 32.12±7.29 ng/mL; 2nd 43.26±9.25 ng/mL; 3rd 45.16±10.70 ng/mL trimester) (p<0.0000)] and preeclamptic women [Leptin (1st 29.91±9.91 ng/mL; 2nd 47.10±25.70 ng/mL; 3rd 63.00±3012 ng/mL trimester) (p<0.0000); sOB-r (1st 32.09±6.97 ng/mL; 2nd 37.54±6.33 ng/mL; 3rd 36.96±7.66 ng/mL trimester) (p=0.0380)].Serum leptin levels were significantly higher in preeclamptic pregnant women compared to healthy pregnant women at 2nd (p=0.029) and 3rd trimesters of pregnancy (p<0.000). Additionally, serum sOB-r levels were also significantly lower in pre - eclamptic pregnant women during the 2nd (p=0.017) and 3rd trimester (p=0.0036) of pregnancy compared to healthy pregnant women. As a result, the FLI index did not vary significantly during any of the three periods of pregnancy studied in healthy pregnant women [(1st 7.99±4.85; 2nd 8.72±6.5; 3rd 9.15±5.84 trimester) (p >0.05)], whereas, in contrast, this index markedly increased throughout pregnancy in pre - eclamptic women [(1st 8.69±4.96; 2nd 13.54±8.78; 3rd 18.06±10.35 trimester) (p=0.0044)]. Indeed, the FLI index was significantly higher at 2nd (p=0.0186) and 3rd (p<0.000) trimesters of pregnancy in pre - eclamptic women compared to healthy pregnant.ConclusionsThe present results demonstrate for the first time in a longitudinal study that FLI increases significantly in pre - eclamptic pregnant women towards the end of pregnancy. Hence, high FLI index values should be further explored as a potentially valuable indicator for the clinical manifestations of this pathology.

Neural regulation of energy and bone homeostasis by the synaptic adhesion molecule Calsyntenin-3

Neuronal regulation of energy and bone metabolism is important for body homeostasis. Many studies have emphasized the importance of synaptic adhesion molecules in the formation of synapses, but their roles in physiology still await further characterization. Here, we found that the synaptic adhesion molecule Calsyntenin-3 (CLSTN3) regulates energy and bone homeostasis. Clstn3 global knockout mice show reduced body mass with improved leptin sensitivity and increased energy expenditure compared to their wild-type littermates. In addition, Clstn3 knockout mice show reduced marrow volume and cortical bone mass without alteration of trabecular bone microarchitecture. This reduced bone mass is not bone cell-autonomous because neither osteoblast- nor osteoclast-specific Clstn3 knockout mice show bone defects; similarly, in vitro cultures of both Clstn3 knockout osteoblasts and osteoclasts do not show any defects. These reduced body and bone mass phenotypes can be attributed instead to neuronal CLSTN3 because they are recapitulated by pan-neuronal but not sympathetic neuron-specific deletion of Clstn3. This study reveals novel physiological functions of neuronal Clstn3 as a key regulator of energy and bone homeostasis.

Pharmacological Strategies for Insulin Sensitivity in Obesity and Cancer: Thiazolidinediones and Metformin.

Chronic diseases, such as obesity and cancer, have high prevalence rates. Both diseases have hyperinsulinemia, hyperglycemia, high levels of IGF-1 and inflammatory cytokines in common. Therefore, these can be considered triggers for cancer development and growth. In addition, low-grade inflammation that modulates the activation of immune cells, cellular metabolism, and production of cytokines and chemokines are common in obesity, cancer, and insulin resistance. Pharmacological strategies are necessary when a change in lifestyle does not improve glycemic homeostasis. In this regard, thiazolidinediones (TZD) possess multiple molecular targets and regulate PPARγ in obesity and cancer related to insulin resistance, while metformin acts through the AMPK pathway. The aim of this study was to review TZD and metformin as pharmacological treatments for insulin resistance associated with obesity and cancer. Thiazolidinediones restored adiponectin secretion and leptin sensitivity, reduced lipid droplets in hepatocytes and orexigen peptides in the hypothalamus. In cancer cells, TZD reduced proliferation, production of reactive oxygen species, and inflammation by acting through the mTOR and NFκB pathways. Metformin has similar effects, though these are AMPK-dependent. In addition, both drugs can be efficient against certain side effects caused by chemotherapy.

Leptin: Less Is More.

The successful use of leptin for the treatment of individuals with lipodystrophy and leptin deficiency is well established. However, pharmacological approaches of leptin therapy for the treatment of diet-induced obesity have been ineffective. There is ample room for a better understanding of the much famed "leptin resistance" phenomenon. Our recent data in this area prompt us to call for a conceptual shift. This shift entails a model in which a reduction of bioactive leptin levels in the context of obesity triggers a high degree of leptin sensitization and improved leptin action, both centrally and peripherally. Put another way, hyperleptinemia per se causes leptin resistance and associated metabolic disorders. In this perspective, we briefly discuss the underlying conceptual steps that led us to explore partial leptin reduction as a viable therapeutic avenue. We hope this discussion will contribute to potential future applications of partial leptin reduction therapy for the treatment of obesity and type 2 diabetes.

Partial leptin deficiency confers resistance to diet-induced obesity in mice

ObjectiveHyperleptinemia per se is sufficient to promote leptin resistance in the obese state. Leptin sensitivity can be restored by reducing circulating leptin levels within a physiologically healthy range and is a viable antiobesity and antidiabetic strategy. However, a previous study suggests that partial leptin deficiency favors diet-induced obesity and related metabolic disorders in mice, arguing that a lower leptin level may indeed promote diet-induced obesity and its associated metabolic disorders. Here, we aim to elucidate what the impact of partial leptin deficiency is on fat mass and insulin sensitivity. MethodsWe used two different mouse models of partial leptin deficiency: an adipocyte-specific congenital heterozygous leptin knockout mouse line (LepHZ) and the well-established whole body heterozygous leptin knockout mouse (OBHZ). The metabolic studies of OBHZ and LepHZ mice were performed both on normal carbohydrate-rich chow diet and on a high-fat diet (HFD). Male and female mice were included in the study to account for sex-specific differences. Body weight, food intake, glucose tolerance, and insulin tolerance were tested. Histology of adipose tissue and liver tissue allowed insights into adipose tissue inflammation and hepatic triglyceride content. Immunohistochemistry was paired with RT-PCR analysis for expression levels of inflammatory markers. ResultsBoth OBHZ and LepHZ mice displayed reduced circulating leptin levels on the chow diet and HFD. On chow diet, male OBHZ and LepHZ mice showed elevated fat mass and body weight, while their glucose tolerance and insulin sensitivity remained unchanged. However, the inability in partially leptin-deficient mice to fully induce circulating leptin during the development of diet-induced obesity results in reduced food intake and leaner mice with lower body weight compared to their littermate controls. Importantly, a strong reduction of adipose tissue inflammation is observed along with improvements in insulin sensitivity and enhanced glucose tolerance. Additionally, partial leptin deficiency protects the mice from fatty liver and liver fibrosis. Chronically HFD-fed OBHZ and LepHZ mice remain more sensitive to exogenous leptin injection, as reflected by their reduced food intake upon an acute leptin treatment. ConclusionIn response to HFD feeding, the inability to upregulate leptin levels due to partial leptin deficiency protects mice from diet-induced obesity and metabolic dysregulation. Thus, in an obesogenic environment, maintaining lower leptin levels is highly beneficial for both obesity and diabetes management. Chronic leptin reduction represents a viable preventive strategy whose efficacy awaits clinical testing.

Loss of leptin receptor-expressing cells in the hindbrain decreases forebrain leptin sensitivity.

Previous studies indicate that inhibition of food intake by leptin is mediated by an integrated response to activation of hypothalamic and hindbrain receptors. This study tested whether loss of hindbrain leptin receptor signaling changed sensitivity to forebrain leptin. Injections of leptin-conjugated saporin (Lep-Sap) into the medial nucleus of the solitary tract (NTS) were used to destroy hindbrain leptin receptor-expressing neurons of male Sprague-Dawley rats. Controls were injected with saporin conjugated with a nonsense peptide (Blk-Sap). Lep-Sap had no effect on daily food intake or body weight, but expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) in the NTS following a peripheral injection of leptin was abolished 26 days after Lep-Sap injections. To test forebrain leptin sensitivity, Lep-Sap and Blk-Sap rats received third-ventricle injections of 0, 0.05, 0.1, 0.25, or 0.5 μg leptin. Food intake was inhibited by 0.25 and 0.5 μg leptin in Blk-Sap rats, but there was no significant effect of leptin on food intake of Lep-Sap rats. There was no difference in hypothalamic pSTAT3 in unstimulated conditions, but pSTAT3 was lower in the dorsomedial region of the ventromedial nucleus of the hypothalamus (VMH) of Lep-Sap rats compared with Blk-Sap rats following a third-ventricle injection of 0.25 μg leptin. These results are consistent with previous data showing that loss of VMH leptin receptor-expressing cells prevents weight loss caused by fourth-ventricle leptin infusion and show that the integrated response between the hindbrain and forebrain is heavily dependent on leptin activity in the VMH.

Beneficial effects of tamoxifen on leptin sensitivity in young mice fed a high fat diet: Role of estrogen receptor α and cytokines

Beneficial effects of tamoxifen on leptin sensitivity in young mice fed a high fat diet: Role of estrogen receptor α and cytokines

Blunted satiety in fatty Zucker rats

Levels of weight gain have hit an epidemic level with rates of overweight and obesity diagnoses topping all-time highs. Elevated body weight has been linked to increased rates of cardiac problems, blood pressure issues, and risk of developing type 2 diabetes. Leptin, a hormone produced by the body that is involved in energy balance by inhibiting hunger has been implicated as an underlying mechanism that differentially contributes to food-seeking motivation. Using a scientifically validated animal model of obesity, the fatty Zucker rat, which has mutated leptin receptor genes, leptin’s role in behavioral motivation can be assessed. Animals were on a 2 -h food access restriction with one-hour access to rewards in session and one hour of free-feeding access. Pre-session and post-session food access differences were evaluated in looking at motivation for food rewards during satiation while responding on differing levels of fixed-ratio schedules. The results showed robust differential behavior from satiation, demonstrating a basis for a biological mechanism involving leptin sensitivity that could underlie obesity. Although further experimentation is needed, understanding leptin could help bridge the gap in our understanding of satiation and non-satiation.

Aging is associated with loss of beneficial effects of estrogen on leptin responsiveness in mice fed high fat diet: Role of estrogen receptor α and cytokines

Aging causes changes in body composition and energy balance. Estrogen plays an important role in body’s metabolism. The aim of this study was to determine whether estrogen has beneficial effects on leptin responsiveness in aged mice. Young 4 months and aged 19–21 female mice fed High Fat Diet (HFD) or Standard Diet (SD) for 12 weeks and following received estrogen for 4 weeks. Responsiveness to leptin was compared by measuring energy balance parameters. Results showed that HFD caused weight gain compared to SD in young, but had no effect on aged animals. Estrogen reduced body weight, energy intake and visceral fat in young, while none of these parameters was affected in aged animals. Although there was leptin sensitivity in aged compared to ovariectomized animals, estrogen only improved the sensitivity of young to leptin. Estrogen prevented increase in TNF-α and a decrease in IL-10 in HFD young and aged animals. Response to estrogen depended on age, and estrogen increased leptin sensitivity only in young animals. Determining the exact mechanism of this action is suggested in future studies.

The reliability of leptin immunostain use for differentiating renal oncocytoma and chromophobe renal cell carcinoma

Background The discrimination between chromophobe renal cell carcinoma (ChRCC) and renal oncocytoma (RO) has been a topic of concern in medicine. Because ChRCC is a malignant tumor, whereas RO is a tumor with benign behavior, it is important to distinguish these two entities. We aimed to study the possible differentiation concepts between ChRCC and RO. Aim We attempted to study the pathological features of RO and ChRCC and correlate them focusing on the reliability of leptin immunostain use as a tool in differentiation. Materials and methods A total of 25 cases of renal tumors (17 RO cases and eight ChRCC ones) were studied for clinicopathological features’ correlation and leptin immunohistochemical expression. Results The included cases’ mean±SD age was 53.1±12.7 years, with range of 28–72 years. The male sex slightly exceeded the female one in prevalence of studied renal neoplasms (52 vs. 48%, respectively). Regarding the size of oncocytoma tumors in gross examination, it had a mean±SD of 5±2 cm, whereas that of ChRCC was 7±4 cm. The central scar is present in only four (23.5%) cases of oncocytoma, being absent in most cases (13 cases, 76.5%). In ChRCC, the nuclear grade 2 is the most common in the studied group (62.5%). Regarding leptin immunostaining scores, positive score was found in 13/17 oncocytoma cases, and only 2/8 cases of ChRCC showed nuclear leptin stain, with significant P value of 0.028. Oncocytoma leptin-positive cases represented 86.70%, whereas those of ChRCC represented 13.30% of total cases. Leptin sensitivity was estimated to be 76.5%, specificity 75.0%, positive predictive value 86.7%, negative predictive value 60.0%, with overall accuracy of 76%. Conclusion Leptin immunostain can be of an extreme help in differentiating ChRCC and RO.

Anagliptin suppresses diet-induced obesity through enhancing leptin sensitivity and ameliorating hyperphagia in high-fat high-sucrose diet fed mice.

Obesity is a major risk factors for type 2 diabetes, and weight loss is beneficial to diabetic patients who are obese or overweight. Dipeptidyl peptidase-4 (DPP-4) inhibitors are anti-diabetic drugs. Although it has been known that the effect of most of the DPP-4 inhibitors on body weight is neutral, several studies suggested that some DPP-4 inhibitors suppressed body weight. Nonetheless, the mechanisms underlying DPP-4 inhibitor-induced weight loss are not fully understood. In this study, the mice fed high-fat high sucrose diet (HFHSD) containing a DPP4 inhibitor, anagliptin, showed reduced food intake and body weight compared to the mice fed non-treated HFHSD, but oxygen consumption and respiratory exchange ratio (RER) were not altered. Sequential administration of leptin suppressed food intake and body weight more apparently in anagliptin treated HFHSD fed mice than non-treated HFHSD fed mice. Oxygen consumption and RER were comparable between anagliptin treated and non-treated mice after leptin administration. The number of phospho STAT3 expressed cells in the arcuate nucleus after leptin administration was increased in anagliptin treated mice compared to non-treated mice. These data suggested that anagliptin ameliorated leptin resistance induced by HFHSD and thereby decreased food intake and body weight. These effects of anagliptin could be beneficial to the treatment of obese diabetic patients.