Increased Plasma Leptin Levels Research Articles

Maternal choline supplementation mitigates premature foetal weight gain induced by an obesogenic diet, potentially linked to increased amniotic fluid leptin levels in rats.

Placental leptin may impact foetal development. Maternal overnutrition has been linked to increased plasma leptin levels and adverse effects on offspring, whereas choline, an essential nutrient for foetal development, has shown promise in mitigating some negative impacts of maternal obesity. Here, we investigate whether a maternal obesogenic diet alters foetal growth and leptin levels in the foetal stomach, amniotic fluid (AF), and placenta in late gestation and explore the potential modulating effects of maternal choline supplementation. Female rats were fed a control (CD) or a western diet (WD) four weeks before mating and during gestation, half of them supplemented with choline (pregnancy days 11-17). Leptin levels (in foetal stomach, AF, and placenta) and leptin gene expression (in placenta) were assessed on gestation days 20 and 21. At day 20, maternal WD feeding resulted in greater leptin levels in foetal stomach, placenta, and AF. The increased AF leptin levels were associated with a premature increase in foetal weight in both sexes. Maternal choline supplementation partially prevented these alterations, but effects differed in CD dams, causing increased AF leptin levels and greater weight in male foetuses at day 20. Maternal choline supplementation effectively mitigates premature foetal overgrowth induced by an obesogenic diet, potentially linked to increased AF leptin levels. Further research is needed to explore the sex-specific effects.

Leptin-dependent gene expression and function in mouse kidney

Objective: Leptin regulates energy balance via leptin receptor expressed in central and peripheral tissues. Little is known about leptin receptor (Lepr)-mediated kidney gene expression and function. Here, we determined kidney gene expression of Lepr splice variants, leptin-sensitive kidney gene expression, and the role of Lepr in renal tubular cells for the response to a high fat diet. Methods: A) Four groups of male mice were used for urine/plasma analysis, and kidney cortex RNA-seq and quantitative RT-PCR (qPCR) analysis: BTBR wild-type, BTBR ob/ob-vehicle (BTBR background in ob/ob promotes diabetic kidney disease), BTBR ob/ob-chronic leptin replacement [6 days via osmotic mini-pump, 4.7 μg/day], and BTBR ob/ob-acute leptin replacement [single dose of 5 mg/kg body weight i.p. and analysis after 7 hours]; all 12-19 weeks old; n=4~15/group. B) Tubular Lepr knockdown (Pax8-Lepr KO) mice were generated by the Pax8-Cre/loxP system, and 5-week old male Pax8-Lepr KO and littermate control mice (n=8-12/group) were fed either control diet or high fat diet (60 kcal% fat) for 35 weeks. Lepr in situ hybridization and qPCR were performed in kidney tissue, and physiological parameters and urinary albumin to creatinine ratio (UACR) were determined. Results: qPCR analysis of Lepr splice variants A, B and C in BTBR mouse kidney revealed a ratio of ~100:10:1 in cortex and medulla with medullary levels being ~10x higher vs cortex with little effects of leptin deficiency (ob/ob)/or replacement. Chronic leptin replacement in ob/ob mice reduced hyperphagia, hyperglycemia and albuminuria, associated with normalization of kidney mRNA expression of molecular markers of glycolysis, gluconeogenesis, amino acid synthesis and megalin. Acute leptin replacement was ineffective implicating indirect metabolic effects for albuminuria in leptin deficiency. Tubular knockdown of Lepr and in situ hybridization indicated that a minor fraction of kidney Lepr mRNA is expressed by tubular cells compared with interstitial or endothelial cells. Nonetheless, Pax8-Lepr KO mice had 13% lower kidney weight (P=0.038). Moreover, they presented similar high fat diet-induced increases in plasma leptin levels, body and kidney weight, and GFR vs controls but a 50% reduced rise in UACR (P=0.0005). Two additional leptin or tubular Lepr-sensitive genes were identified: Leptin deficiency and tubular Lepr knockdown reduced renal expression of acetoacetyl-CoA synthetase (AACS) and increased expression of gremlin 1 (Grem1), while leptin replacement in ob/ob induced opposite effects. Conclusions: Leptin deficiency may increase albuminuria via systemic metabolic effects that impinge on kidney megalin expression. Hyperleptinemia-induced albuminuria may involve direct effects via tubular Lepr. Implications of the novel tubular Lepr/AACS/Grem1 axis and of Lepr variants remain to be determined. This study was supported by Janssen Pharmaceuticals, Inc. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

OBESE MICE WITH PNEUMONIA HAVE HYPERLEPTINEMIA AND INCREASED PULMONARY SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 ACTIVATION.

Obesity is an ongoing epidemic that influences pathobiology in numerous disease states. Obesity is associated with increased plasma leptin levels, a hormone that activates the signal transducer and activator of transcription 3 (STAT3) pathway. Pneumonia is a significant cause of morbidity and mortality. During pneumonia, inflammatory pathways including STAT3 are activated. Outcomes in obese patients with pneumonia are mixed, with some studies showing obesity increases harm and others showing benefit. It is unclear whether obesity alters STAT3 activation during bacterial pneumonia and how this might impact outcomes from pneumonia. We used a murine model of obesity and pneumonia challenge with Pseudomonas aeruginosa in obese and nonobese mice to investigate the effect of obesity on STAT3 activation. We found obese mice with bacterial pneumonia had increased mortality compared with nonobese mice. Inflammatory markers, IL-6 and TNF-α, and lung neutrophil infiltration were elevated at 6 h after pneumonia in both nonobese and obese mice. Obese mice had greater lung injury compared with nonobese mice at 6 h after pneumonia. Leptin and insulin levels were higher in obese mice compared with nonobese mice, and obese mice with pneumonia had higher pulmonary STAT3 activation compared with nonobese mice.

Butyrate Protects against Diet-Induced NASH and Liver Fibrosis and Suppresses Specific Non-Canonical TGF-β Signaling Pathways in Human Hepatic Stellate Cells.

In obesity-associated non-alcoholic steatohepatitis (NASH), persistent hepatocellular damage and inflammation are key drivers of fibrosis, which is the main determinant of NASH-associated mortality. The short-chain fatty acid butyrate can exert metabolic improvements and anti-inflammatory activities in NASH. However, its effects on NASH-associated liver fibrosis remain unclear. Putative antifibrotic effects of butyrate were studied in Ldlr-/-.Leiden mice fed an obesogenic diet (HFD) containing 2.5% (w/w) butyrate for 38 weeks and compared with a HFD-control group. Antifibrotic mechanisms of butyrate were further investigated in TGF-β-stimulated primary human hepatic stellate cells (HSC). HFD-fed mice developed obesity, insulin resistance, increased plasma leptin levels, adipose tissue inflammation, gut permeability, dysbiosis, and NASH-associated fibrosis. Butyrate corrected hyperinsulinemia, lowered plasma leptin levels, and attenuated adipose tissue inflammation, without affecting gut permeability or microbiota composition. Butyrate lowered plasma ALT and CK-18M30 levels and attenuated hepatic steatosis and inflammation. Butyrate inhibited fibrosis development as demonstrated by decreased hepatic collagen content and Sirius-red-positive area. In TGF-β-stimulated HSC, butyrate dose-dependently reduced collagen deposition and decreased procollagen1α1 and PAI1 protein expression. Transcriptomic analysis and subsequent pathway and upstream regulator analysis revealed deactivation of specific non-canonical TGF-β signaling pathways Rho-like GTPases and PI3K/AKT and other important pro-fibrotic regulators (e.g., YAP/TAZ, MYC) by butyrate, providing a potential rationale for its antifibrotic effects. In conclusion, butyrate protects against obesity development, insulin resistance-associated NASH, and liver fibrosis. These antifibrotic effects are at least partly attributable to a direct effect of butyrate on collagen production in hepatic stellate cells, involving inhibition of non-canonical TGF-β signaling pathways.

Endothelial mineralocorticoid receptor deletion ablates leptin‐induced cardiovascular and fetal growth preeclampsia characteristics in pregnant mice

Obesity increases the risk for preeclampsia (PE), a hypertensive syndrome of pregnancy characterized by placental ischemia. Obese PE patients demonstrate increases in plasma leptin levels in midgestation due to increased placental leptin production. We have shown that pregnancy increases endothelial mineralocorticoid receptor (ECMR) expression and that ECMR mediates leptin-induced endothelial dysfunction and hypertension in nonpregnant females. We therefore hypothesized that ECMR deletion protects from the development endothelial dysfunction, hypertension and fetal growth restriction in pregnant leptin-infused mice. Pregnant ECMR+/+ (WT) and ECMR-/- (KO) littermate mice were infused with vehicle or leptin (N=4-6/group) by osmotic minipump (0.9mg/kg/day, s.c.) from GD11-18 and thoracic aortas assessed for vascular function by wire myography. Separate groups (N=1-2/group) were implanted with radiotelemeters for systolic blood pressure (BP) measurement. Leptin decreased pup weight (0.86±0.04g WT vs 0.52±0.11g WT+lep, *P<0.05) and placental efficiency (9.7±0.7 WT vs 7.9±0.6 WT+lep, pup/placenta weight ratio, *P<0.05) indicating fetal growth restriction. ECMRdeletion prevented leptin-mediated decreases in pup weight (0.91±0.06g KO vs 1.0±0.07g KO+lep) and placental efficiency (9.6±0.5 KO vs 9.4±1.2 KO+lep). Preliminary data shows that prior to leptin infusion (GD8-11) all groups demonstrated similar BP and circadian rhythm of BP. Leptin infusion increased BP and ablated circadian rhythm (GD11-18, 114 mmHg WT vs 137 mmHg WT+lep), however, ECMR deletion blunted leptin-induced BP increases (112 KO mmHg vs 120 mmHg KO+lep) and preserved circadian rhythm. Leptin infusion reduced endothelial function (acetylcholine-mediated relaxation) in aortas of WT, but not KO, pregnant mice (2-way ANOVA, repeated measures, *P<0.05). Relaxation to acetylcholine with LNAME showed restoration of endothelial function in KO+lep mice was NO-dependent. In addition, ECMR deletion protected pregnant mice from leptin-induced increases in vascular α1 receptor-mediated constriction (phenylephrine) (*P<0.05). Endothelial-independent relaxation to sodium nitroprusside was similar across all groups. Moreover, ECMR deletion protected from leptin-mediated increases in placental mRNA expression of: sFlt-1 (WT+leptin: 1.2±0.03-fold from WT, *P<0.05, KO+leptin: 1.1±0.1-fold change from KO), HIF1α (WT+leptin: 1.6±0.1-fold, P=0.09, KO+leptin: 1.5±0.2-fold) and galectin 3 (WT+leptin: 3.2±0.5-fold, *P<0.05, KO+leptin: 0.8±0.1-fold). Collectively, these data indicate that ECMR deletion decreases BP, improves vascular function and placental function in association with increased vascular NO bioavailability and fetal growth in an obesity-associated, leptin-infusion model of PE.

1-trifluoromethoxyphenyl-3(1-propionylpiperidin-4-yl) urea (TPPU), a soluble epoxide hydrolase inhibitor attenuates high fat diet-induced cardiovascular and metabolic disorders in rats.

Obesity was induced in rats by feeding on a high fat diet (HFD), 60% w/w cholesterol, 20% w/w carbohydrates, and 20% w/w proteins for two months. Animals were fed on a HFD and treated concurrently with a single daily dose of vehicle or TPPU (2 mg/kg p.o) for two months. Body weights, blood pressure, and biochemical investigations of all animals were registered at 0, 1, and 2 months of the experimental period. Vehicle-treated rats fed on a HFD had a considerable increase in body weight compared to age-matched control animals fed on a regular diet (regular diet; 311.40 ±9.60 vs. HFD; 446 ± 12.67). The body weight of rats fed on a HFD and concurrently treated with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4yl) urea (TPPU; 2 mg/kg p.o) daily for two months was significantly decreased (p<0.01). A significant (p<0.01) increase in the systolic blood pressure of animals and vascular dysfunction with blunted relaxant response to acetylcholine and sodium nitroprusside was evident in vehicle-treated animals fed on a HFD compared to control rats fed on a regular diet. These HFD-induced disorders were markedly attenuated in animals fed on a HFD and treated concurrently with a single daily dose of TPPU (2 mg/kg p.o). HFD diet-induced deleterious metabolic changes were prevented with concurrent administration of TPPU (2 mg/kg p.o). TPPU treatment decreased the HDF-induced increase in plasma creatinine levels (p<0.001) in rats. The adiponectin levels were decreased (p<0.001) in vehicle-treated rats fed on HFD for two months compared to control rats fed on a normal diet (p<0.001). Adiponectin levels were significantly (p<0.001) increased in rats fed on HFD and treated concurrently with TPPU (2 mg/kg p.o). HFD diet caused a marked increase in plasma leptin levels of animals which were significantly decreased in animals fed on a HFD and treated concurrently with TPPU for two months. Obese animals exhibited increased levels of plasma insulin compared to control animals fed on a regular diet which were significantly suppressed (p<0.001) by TPPU treatment. In the current investigation, TPPU treatment had a favorable impact on the levels of other metabolic parameters such as plasma cholesterol, triglycerides (TGs), low density lipoproteins (LDLs), and high density lipoproteins (HDL). HFD caused a profound increase in the serum liver enzymes, the effect was reversed by treatment of animals with TPPU (2 mg/kg p.o). The findings of our current study indicate the promising therapeutic potential of TPPU as a new drug candidate to manage obesity-induced cardiovascular and metabolic disorders. Soluble epoxide hydrolase inhibitors such as TPPU could prevent HFD-induced obesity and related cardiovascular and metabolic complications.

Continuous and Discontinuous Adherence to the Sticky Japanese Diet on Adiponectin and Leptin Regulation

Background: In order to evaluate the regulational role of adiponectin and leptin on obesity, we examined the significance of daily adherence to the Sticky Japanese Diet (SJD) on the preventions of obesity and metabolic syndrome by assessing the fat adiponectin/leptin and plasma leptin levels using normal and high-fat diet (HFD) mice. Methods: Five-week-old male ICR strain mice were placed in individual cages and randomly divided into eight groups based on feeding of SJD or not. At the end of each treatment period, plasma triglyceride, cholesterol, and leptin levels were measured by biochemical analysis. The adiponectin and leptin levels in adipose tissue were measured using RT-PCR. Results: In normal mice, an eight-week treatment of SJD increased adiponectin levels in adipose tissue. However, four weeks after discontinuing the SJD, these levels decreased. Furthermore, continuous feeding of the SJD for eight weeks increased plasma leptin levels but not that of adipose tissue. And then, discontinuing the SJD for more than eight days resulted in a decrease in plasma leptin levels. In HFD mice, an increase in body weight and visceral fat was seen at eight days after discontinuing the SJD which was undertaken for a total of eight weeks. At this time, the plasma leptin levels in these mice were substantially higher than in normal mice, although these levels were getting to be decreased over four weeks. Conclusion: This study revealed that discontinuous adherence to the SJD induced decreases in both adiponectin and leptin levels. Together with our previous publication, this paper suggests that daily adherence to the SJD might be essential for maintaining good health. Keywords: NuruNeba (Sticky Japanese Diet); Washoku (Japanese foods); normal diet; high-fat diet; leptin; adiponectin; obesity; mice Abbreviations: SJD: Sticky Japanese Diet; HFD: High-Fat Diet; CE-2: CLEA Rodent Diet CE-2; TG: Triglyceride; UCP1: Uncoupling Protein-1; BAT: Brown Adipose Tissue

Consumption of lycopene-rich tomatoes improved glucose homeostasis in rats via an increase in leptin levels.

The lycopene content of tomatoes is important because of its effects on vital physiological functions such as improvement of glucose tolerance and non-alcoholic fatty liver disease. To investigate the influence of the lycopene content of tomatoes on glucose tolerance and hepatic lipid content, homogenates of lycopene-rich (LR) or lycopene-free negative control (NC) tomato varieties were administrated to normal rats for 4weeks. At the end of the experiment, an oral glucose tolerance test (OGTT) was performed. Rats were fed once and then dissected. According to the OGTT results, plasma glucose levels in the LR group were 10% and 9% lower at 15min and 30min, respectively, than those in the NC group, whereas plasma insulin levels did not differ between the groups at either time point. Upon dissection, plasma leptin levels in the LR group were higher than those in the NC group, while plasma adiponectin levels did not differ between groups. With the exception of retinol palmitate, no carotenoids were detected in the liver by HPLC analysis. Hepatic retinol palmitate levels and hepatic triacyl glyceride levels did not differ between the groups. We concluded that in normal rats, a lycopene-rich tomato variety improved glucose tolerance via an increase in plasma leptin levels that enhanced insulin sensitivity but did not affect carotenoid accumulation or lipid metabolism.

FoxO1 Is Required for Most of the Metabolic and Hormonal Perturbations Produced by Hepatic Insulin Receptor Deletion in Male Mice.

Insulin coordinates the complex response to feeding, affecting numerous metabolic and hormonal pathways. Forkhead box protein O1 (FoxO1) is one of several signaling molecules downstream of insulin; FoxO1 drives gluconeogenesis and is suppressed by insulin. To determine the role of FoxO1 in mediating other actions of insulin, we studied mice with hepatic deletion of the insulin receptor, FoxO1, or both. We found that mice with deletion of the insulin receptor alone showed not only hyperglycemia but also a 70% decrease in plasma insulin-like growth factor 1 and delayed growth during the first 2 months of life, a 24-fold increase in the soluble leptin receptor and a 19-fold increase in plasma leptin levels. Deletion of the insulin receptor also produced derangements in fatty acid metabolism, with a decrease in the expression of the lipogenic enzymes, hepatic diglycerides, and plasma triglycerides; in parallel, it increased expression of the fatty acid oxidation enzymes. Mice with deletion of both insulin receptor and FoxO1 showed a much more modest phenotype, with normal or near-normal glucose levels, growth, leptin levels, hepatic diglycerides, and fatty acid oxidation gene expression; however, lipogenic gene expression remained low. Taken together, these data reveal the pervasive role of FoxO1 in mediating the effects of insulin on not only glucose metabolism but also other hormonal signaling pathways and even some aspects of lipid metabolism.

Gastrointestinal Peptides During Chronic Gastric Electrical Stimulation in Patients With Intractable Vomiting

Gastric electrical stimulation (GES) is an alternative therapy to treat patients with intractable vomiting. A preclinical study has demonstrated the modulation of the gastrointestinal (GI) peptide ghrelin by GES but such mechanism has never been investigated in patients. The aim of this work was to assess the effect of GES on GI peptide levels in patients with intractable vomiting. Twenty-one patients were randomized to receive either ON or OFF GES, 14 completed the study (10 ON, 4 OFF stimulation). Vomiting episodes, gastric emptying, and gastrointestinal quality of life index (GIQLI) were assessed. Gastric and blood samples were collected before and four months after the ON period of gastric stimulation. mRNA and/or peptide levels were assessed in gastric biopsies for ghrelin, leptin, and NUCB2/nesfatin-1 and in duodenal biopsies for glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) using RT-qPCR and multiplex technology. Ghrelin, leptin, GLP-1, PYY, gastric inhibitory peptide (GIP), and NUCB2/nesfatin-1 levels also were quantified in blood samples. Among clinical parameters, vomiting episodes were slightly reduced by GES (p = 0.09). In tissue, mRNA or protein levels were not modified following chronic GES. In blood, a significant reduction of postprandial PYY levels (p < 0.05) was observed at M4 and a reduction of NUCB2/nesfatin-1 levels in fasted patients (p < 0.05). Increased plasma leptin levels after GES were correlated with reduction of vomiting and improvement of GIQLI. GES reduces NUCB2/nesfatin-1 levels under fasting conditions and postprandial PYY levels in patients suffering from nausea and/or vomiting refractory to pharmacological therapies.

Masked Hypertension–A Systematic Review

Background/Aim: The significance of Masked Hypertension(MHT) and Masked Uncontrolled Hypertension(MUCH) in clinical practice is unclear. We systematically reviewed the literature on MHT and MUCH, with a particular focus on prevalence, epidemiology, pathogenesis, clinical significance, evaluation and management. Methods: Medline(OvidSP), PubMed and Cochrane databases were searched for articles published in English from 2000 to 6th Jan 2017 using the MeSH terms and keywords “MHT”, “MUCH”, “Reversed white coat hypertension”, “out of office hypertension”, “Ambulatory hypertension”, and “white coat normotension”. All but publications in paediatric age group, case reports, editorials and narrative reviews were included. Results: 240 articles met the inclusion criteria: 92(epidemiology); 7(pathogenesis); 93(clinical significance); 74(evaluation) and 7(management). The prevalence of MHT/MUCH was variably reported(5.7%-32.1%). Potential risk factors included older age; male gender; African inheritance; mental stress; tobacco, alcohol and caffeine use: obstructive sleep apnoea(OSA); diabetes; chronic kidney disease; hypothyroidism; treatment of hypertension and a high office BP, ambulatory pulse rate and BMI. The pathogenesis of MHT/MUCH is unclear, although it was associated with endothelial dysfunction, oxidative stress, increased plasma leptin levels and sympathetic activity. MHT conferred similar cardiovascular risk as sustained hypertension; increased cardiovascular morbidity/mortality and target organ damage. Ambulatory BP monitoring was the preferred diagnostic method although Home BP monitoring was a useful alternative. Anecdotal evidence supports risk factor modification(OSA), however the evidence for drug treatment of MHT is scant. Conclusion: MHT/MUCH is widely prevalent. Patients with high normal clinic BP should be screened for MHT/MUCH. RCTs are needed to assess the efficacy of drug treatment of MHT.

Injections of Galanin-Like Peptide directly into the nucleus of the tractus solitarius (NTS) reduces food intake and body weight but increases metabolic rate and plasma leptin

Galanin-Like Peptide (GALP) is a hypothalamic neuromediator of metabolism and reproduction. GALP is known to stimulate reproduction and alter food intake and body weight in multiple species. The regulation of body weight involves control of both energy intake and energy expenditure. Since GALP is known to alter food intake - possibly via the autonomic nervous system - we first hypothesized that GALP would increase metabolic rate. First, male Sprague-Dawley rats were implanted with intracerebroventricular (ICV) cannulae and abdominal radiotelemetry temperature transmitters. Following ICV injection with either 5nmol GALP or vehicle, the oxygen consumption of each rat was monitored for 8h. Food intake, core temperature, and general motor activity were monitored for 24h. GALP significantly increased oxygen consumption, an indirect estimator of metabolic rate, without having any significant effect on motor activity. Compared to controls, GALP increased core body temperature during the photophase and reduced food intake over the 24h period following injection. ICV GALP also increased plasma levels of luteinizing hormone (LH). A second group of male Sprague-Dawley rats were implanted with abdominal transmitters and given injections of GALP directly into the nucleus of the tractus solitarius (NTS). These injections resulted in a significant reduction in food intake, and a significant increase in both oxygen consumption and core body temperature compared to vehicle injections. Direct injections of GALP into the NTS compared to vehicle also resulted in a significant increase in plasma leptin levels, but not LH levels. GALP appears to increase energy expenditure in addition to decreasing energy input by actions within the NTS and thus may play an important role in the hypothalamic regulation of body weight.

Effect of high fat diet on pulmonary expression of parathyroid hormone-related protein and its downstream targets

AimsParathyroid hormone-related protein (PTHrP) is involved in lung development and surfactant production. The latter one requires a paracrine interaction between type II alveolar cells and lipofibroblasts in which leptin triggers PTHrP-induced effects. Whether increased plasma leptin levels, as they occur in high fat diet, modify the expression of PTHrP remains unclear. Furthermore, the effect of high fat diet under conditions of forced pulmonary remodelling such as response to post myocardial infarction remains to be defined.Materials and methodsC57 bl/6 mice were randomized to either normal diet or high fat diet at an age of 6 weeks. Seven months later, the mice were euthanized and the lung was removed and frozen in fluid nitrogen until use. Samples were analyzed by real-time RT-PCR and western blot. Leptin deficient mice were used to investigate the effect of leptin on pulmonary expression of PTHrP more directly. A subgroup of mice with and without high fat diet underwent in vivo ischemia (45 min) and reperfusion (4 weeks). Finally, experiments were repeated with prolonged high-fat diet.Key findingsHigh fat diet increased plasma leptin levels by 30.4% and the pulmonary mRNA expression of PTHrP (1,447-fold), PTH-1 receptor (4.21-fold), and PTHrP-downstream targets ADRP (7.54-fold) and PPARγ (5.27-fold). Pulmonary PTHrP expression was reduced in leptin deficient mice by 88% indicating leptin dependent regulation. High fat diet further improved changes in pulmonary adaptation caused by ischemia/reperfusion (1.48-fold increased PTH-1 receptor protein expression). These effects were lost during prolonged high fat diet.SignificanceThis study established that physiological regulation of leptin plasma levels by high fat diet affects the pulmonary PTHrP expression and of PTHrP downstream targets. Modification of pulmonary expression of PTH-1 receptors by high fat diet after myocardial infarction suggests that the identified interaction may participate in the obesity paradox.

Impact of obesity on functional and laboratory parameters in patients with rheumatoid arthritis

Overweight patients with rheumatoid arthritis (RA) have more disease activity, lower rates of remission, and twice as likely to require a tumor necrosis factor inhibitor. Provided that the prevalence of obesity is increasing, this may significantly affect RA incidence. An association between obesity and RA is logic, as biologic mechanisms of inflammation are present in fatty tissue, and it may be a trigger to chronic systemic inflammation. Human obesity is characterized by increased plasma leptin levels, which if elevated in morbidly obese patients may enhance constitutive immunological stimuli and increased levels of inflammatory marker. The aim of this study was to assess the impact of obesity and serum leptin level on disease activity and functional outcome in RA patients. This study was carried out at Minia University Hospital, Egypt. Patients were recruited from Rheumatology Outpatient Clinic from October 2012 to June 2013. It included 36 RA patients, fulfilling the 2010 ACR/EULAR classification criteria. They were divided into two groups: obese patients with a BMI of 25 or greater and nonobese patients (BMI ≤ 25). A total of 12 healthy individuals were included as controls. All patients were subjected to history taking and clinical examination; patient’s functional status and disease activity were assessed using the Health Assessment Questionnaire (HAQ) disability index and DAS-28, respectively. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and rheumatoid factor (RF) were determined. Serum level of leptin was measured using enzyme-linked immunosorbent assay. Data were analyzed using SPSS for Windows, version 16.0. RA obese patients showed a higher duration of morning stiffness (P = 0.02), HAQ index (P = 0.001), DAS-28 (P = 0.0001), visual analogue scale (VAS) of pain (P = 0.0001), and articular index (P = 0.001) compared with nonobese ones. They showed higher ESR (P = 0.003), serum leptin (P = 0.008), CRP (P = 0.0001), and RF (P = 0.002). There was a positive correlation between BMI and each of ESR (P = 0.003), CRP (P = 0.0001), and RF (P = 0.01). There was a positive correlation between waist circumference and each of ESR (P = 0.03), serum leptin (P = 0.03), CRP (P = 0.0001), and RF (P = 0.04). There was a positive correlation between BMI and HAQ index (P = 0.0001), DAS-28 (P = 0.001), articular index (P = 0.003), and VAS of pain (P = 0.0001). There was a positive correlation between waist circumference and HAQ index (P = 0.001), DAS-28 (P = 0.03), and VAS of pain (P = 0.0001). Moreover, there was a positive correlation between VAS of pain and serum leptin (P = 0.04). Serum leptin was correlated with CRP (P= 0.01). Linear regression analysis showed that the VAS was the first and most significant risk factor (β = 0.73; P = 0.01) and that HAQ was the second (β = –0.53; P = 0.04) to affect serum leptin levels. Obese RA patients had higher disease activity parameters, clinical scores and laboratory indices, and worse functional outcomes compared with nonobese patients. Higher serum leptin levels were associated with higher disease activity scores.

Age-Associated Weight Gain, Leptin, and SIRT1: A Possible Role for Hypothalamic SIRT1 in the Prevention of Weight Gain and Aging through Modulation of Leptin Sensitivity.

The hypothalamus is the principal regulator of body weight and energy balance. It modulates both energy intake and energy expenditure by sensing the energy status of the body through neural inputs from the periphery as well as direct humoral inputs. Leptin, an adipokine, is one of the humoral factors responsible for alerting the hypothalamus that enough energy is stored in the periphery. Plasma leptin levels are positively linked to adiposity; leptin suppress energy intake and stimulates energy expenditure. However, prolonged increases in plasma leptin levels due to obesity cause leptin resistance, affecting both leptin access to hypothalamic neurons and leptin signal transduction within hypothalamic neurons. Decreased sensing of peripheral energy status through leptin may lead to a positive energy balance and gradual gains in weight and adiposity, further worsening leptin resistance. Leptin resistance, increased adiposity, and weight gain are all associated with aging in both humans and animals. Central insulin resistance is associated with similar observations. Therefore, improving the action of humoral factors in the hypothalamus may prevent gradual weight gain, especially during middle age. SIRT1 is a NAD+-dependent protein deacetylase with numerous substrates, including histones, transcription factors, co-factors, and various enzymes. SIRT1 improves both leptin sensitivity and insulin sensitivity by decreasing the levels of several molecules that impair leptin and insulin signal transduction. SIRT1 and NAD+ levels decrease with age in the hypothalamus; increased hypothalamic SIRT1 levels prevent age-associated weight gain and improve leptin sensitivity in mice. Therefore, preventing the age-dependent loss of SIRT1 function in the hypothalamus could improve the action of humoral factors in the hypothalamus as well as central regulation of energy balance.

Effects of early-onset voluntary exercise on adult physical activity and associated phenotypes in mice

The purpose of this study was to evaluate the effects of early-life exercise on adult physical activity (wheel running, home-cage activity), body mass, food consumption, and circulating leptin levels in males from four replicate lines of mice selectively bred for high voluntary wheel running (High Runner or HR) and their four non-selected control (C) lines. Half of the mice were given wheel access shortly after weaning for three consecutive weeks. Wheel access was then removed for 52 days, followed by two weeks of adult wheel access for all mice. A blood sample taken prior to adult wheel testing was analyzed for circulating leptin concentration. Early-life wheel access significantly increased adult voluntary exercise on wheels during the first week of the second period of wheel access, for both HR and C mice, and HR ran more than C mice. During this same time period, activity in the home cages was not affected by early-age wheel access, and did not differ statistically between HR and C mice. Throughout the study, all mice with early wheel access had lower body masses than their sedentary counterparts, and HR mice had lower body masses than C mice. With wheel access, HR mice also ate significantly more than C mice. Early-life wheel access increased plasma leptin levels (adjusted statistically for fat-pad mass as a covariate) in C mice, but decreased them in HR mice. At sacrifice, early-life exercise had no statistically significant effects on visceral fat pad, heart (ventricle), liver or spleen masses (all adjusted statistically for variation in body mass). Results support the hypothesis that early-age exercise in mice can have at least transitory positive effects on adult levels of voluntary exercise, in addition to reducing body mass, and may be relevant for the public policy debates concerning the importance of physical education for children.

Orexin A regulates plasma insulin and leptin levels in a time-dependent manner following a glucose load in mice.

Orexin A (OXA) is a neuropeptide implicated in the regulation of arousal status and energy metabolism. Orexin receptors are expressed not only in the central nervous system but also in the pancreas and adipose tissue. However, little is known about the physiological function of orexins. This study investigated the role of exogenous OXA in blood glucose control after glucose load in mice. In addition, the effect of OXA on insulin secretion was also identified in mouse pancreatic beta cells. Insulin secretion and intracellular Ca(2+) levels were measured in perifused mouse islets. To investigate the effects of exogenous OXA on blood glucose levels in vivo, intraperitoneal glucose tolerance tests were performed after a subcutaneous injection of OXA in normal and high-fat diet-induced diabetic mice. OXA significantly potentiated glucose-stimulated insulin secretion in vitro, which increased intracellular Ca(2+) levels, mainly through adenylate cyclase and ryanodine receptor activation. This Ca(2+)-dependent insulinotropic effect of OXA was blocked in Epac2 (Rapgef4)-deficient beta cells. After a glucose load in mice, exogenous OXA decreased blood glucose levels, compared with the control, by enhancing plasma insulin and decreasing plasma glucagon levels. Additionally, OXA caused a delayed increase in plasma leptin levels, resulting in lower plasma insulin levels when blood glucose levels fell to baseline. These results suggest that OXA might be a critical regulator of insulin, glucagon and leptin secretion in response to glucose. Thus, exogenous OXA might have therapeutic potential in improving blood glucose control in patients with type 2 diabetes.

Efficacy and tolerability of histamine-2 receptor antagonist adjunction of antipsychotic treatment in schizophrenia: a meta-analysis of randomized placebo-controlled trials.

No comprehensive meta-analysis has been performed concerning the efficacy and tolerability of adjunctive therapy with histamine-2 receptor antagonists (H2R-ANTs) in schizophrenia patients who were treated with antipsychotics. Risk ratios, standardized mean differences (SMD), and 95% confidence intervals were calculated. We included 8 double-blinded, randomized placebo-controlled trials (RCTs) (n=418) that met the inclusion criteria (famotidine: N=3, n=74; nizatidine: N=4, n=292; ranitidine: N=1, n=52). Pooled H2R-ANTs were not different from placebo with regard to reduction in overall symptoms and body weight. However, pooled H2R-ANTs resulted in lower body mass index (BMI) than placebo (SMD=-0.68). Moreover, nizatidine was associated with an increase in plasma leptin levels (SMD=-1.14). There were no significant differences in the discontinuation rates due to all-cause, side effects, and inefficacy between pooled H2R-ANTs and placebo. However, nizatidine produced more depression and dry mouth than placebo. H2R-ANT adjunctive therapy did not improve overall symptoms. To clarify the opposite results between body weight and BMI, future research should investigate long-term efficacy and generate more safety data by using larger samples.

Gender-dependent resiliency to stressful and metabolic challenges following prenatal exposure to high-fat diet in the p66(Shc-/-) mouse.

Metabolic stressful challenges during susceptible time windows, such as fetal life, can have important implications for health throughout life. Deletion of the p66Shc gene in mice leads to reduced oxidative stress (OS), resulting in a healthy and lean phenotype characterized by increased metabolic rate, resistance to high-fat diet (HFD)-induced obesity and reduced emotionality at adulthood. Here we hypothesize that p66Shc−/− (KO) adult offspring might be protected from the detrimental effects induced by maternal HFD administered before and during pregnancy. To test such hypothesis, we fed p66Shc+/+ (WT) and KO females with HFD for 13 weeks starting on 5 weeks of age until delivery and tested adult male and female offspring for their metabolic, neuroendocrine, and emotional profile. Prenatal diet affected stress responses and metabolic features in a gender-dependent fashion. In particular, prenatal HFD increased plasma leptin levels and decreased anxiety-like behavior in females, while increasing body weight, particularly in KO subjects. KO mice were overall characterized by metabolic resiliency, showing a blunted change in glycemia levels in response to glucose or insulin challenges. However, in p66Shc−/− mice, prenatal HFD affected glucose tolerance response in an opposite manner in the two genders, overriding the resilience in males and exacerbating it in females. Finally, KO females were protected from the disrupting effect of prenatal HFD on neuroendocrine response. These findings indicate that prenatal HFD alters the emotional profile and metabolic functionality of the adult individual in a gender-dependent fashion and suggest that exposure to high-caloric food during fetal life is a stressful condition interfering with the developmental programming of the adult phenotype. Deletion of the p66Shc gene attenuates such effects, acting as a protective factor.

Preliminary findings on the influence of FTO rs9939609 and MC4R rs17782313 polymorphisms on resting energy expenditure, leptin and thyrotropin levels in obese non-morbid premenopausal women

Given that leptin, ghrelin and thyrotropin play a major role in the regulation of resting energy expenditure (REE) and that the FTO rs9939609 and the MC4R rs17782313 polymorphisms have been proposed to affect energy homeostasis, we hypothesized that both polymorphisms are associated with REE and that these relationships can be mediated by leptin, ghrelin and thyrotropin in obesity. Therefore, the present study aimed to examine the relationships between FTO rs9939609 and the MC4R rs17782313 with REE, leptin, ghrelin and thyrotropin levels in obese women. The study comprised 77 obese (body mass index 34.0 ± 2.8 kg/m(2)) women (age 36.7 ± 7 years). We measured body composition by dual-energy X-ray absorptiometry and REE by indirect calorimetry. We analysed fasting leptin, ghrelin and thyrotropin levels and the ratio of leptin to fat mass was calculated. Genotype distributions of the polymorphisms did not deviate from Hardy-Weinberg expectations (P values >0.2). Women carrying the A allele of the FTO rs9939609 had lower REE (1,580 ± 22 vs. 1,739 ± 35 kcal/day, P < 0.001) and higher leptin to fat mass ratio (1.33 ± 0.05 vs. 1.13 ± 0.08 ng/ml kg, P < 0.05) and thyrotropin levels (1.93 ± 0.10 vs. 1.53 ± 0.16 μU/ml, P < 0.05) regardless of age and body mass index. We found no significant influence of the MC4R rs17782313 on energy metabolism or biochemical variables. Our findings confirm that the A allele of the FTO rs9939609 is associated with lower REE and increased plasma leptin levels. We also found an association between the FTO rs9939609 and thyrotropin, suggesting the possible influence of FTO in the hypothalamic-pituitary-thyroid axis as a potential mechanism of the increased adiposity.