Induced Weight Gain Research Articles

Kisspeptin Neurons in the Arcuate Nucleus of the Hypothalamus Orchestrate Circadian Rhythms and Metabolism

Successful reproduction in female mammals is precisely timed and must be able to withstand the metabolic demand of pregnancy and lactation. We show that kisspeptin-expressing neurons in the arcuate hypothalamus (Kiss1ARH) of female mice control thedaily timing of food intake, along with the circadian regulation of locomotor activity, sleep, and core body temperature. Toxin-induced silencing of Kiss1ARH neurons shifts wakefulness and food consumption to the light phase and induces weight gain. Toxin-silenced mice are less physically active and have attenuated temperature rhythms. Because the rhythm of the master clock in the suprachiasmatic nucleus (SCN) appears to be intact, we hypothesize that Kiss1ARH neurons signal to neurons downstream of the master clock to modulate the output of the SCN. We conclude that, in addition to their well-established role in regulating fertility, Kiss1ARH neurons are a critical component of the hypothalamic circadian oscillator network that times overt rhythms of physiology and behavior.

Continuation of structure-activity relationship study of novel benzamide derivatives as potential antipsychotics.

A series of benzamide derivatives possessing potent dopamine D2 , serotonin 5-HT1A , and 5-HT2A receptor properties were synthesized and evaluated as potential antipsychotics. Among them, 5-(4-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)butoxy)-N-cyclopropyl-2-fluorobenzamide (4k) held the best pharmacological profile. It not only exhibited potent and balanced activities for the D2 , 5-HT1A , and 5-HT2A receptors, but was also endowed with low to moderate activities for the 5-HT2C , H1 , and M3 receptors, suggesting a low propensity for inducing weight gain or diabetes. In animal models, compound 4k reduced phencyclidine-induced hyperactivity with a high threshold for catalepsy or muscle relaxation induction. On the basis of its robust in vitro potency and in vivo efficacy in preclinical models of schizophrenia, 4k was selected as a candidate for further development.

Effects of antipsychotic therapy on lipid and carbohydrate metabolism of schizophrenic patients

Atypical antipsychotic drugs such as Olanzapine (Ola) induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying these undesired side-effects are currently unknown. Chagnon et al. showed that the common allele rs7973796 of the prepro-melanin-concentrating hormone (PMCH) gene is associated with a greater body mass index in Ola-treated schizophrenic patients. As PMCH encodes for the orexigenic neuropeptide melanin-concentrating hormone (MCH), it was hypothesized that MCH is involved in Ola-induced metabolic changes. We have recently reported that the intragastric infusion of Ola results in hyperglycaemia and insulin resistance in male rats. In order to test in vivo the possible involvement of the PMCH gene in the pathogenesis of Ola side-effects, we administered Ola intragastrically in wild-type (WT) and PMCH knock-out (KO) rats. Our results show that glucose and corticosterone levels, as well as endogenous glucose production, are elevated by the infusion of Ola in both WT and KO animals. Thus, the lack of MCH does not seem to affect the acute effects of Ola on glucose metabolism. On the other hand, these effects might be obliterated by compensatory changes in other hypothalamic systems. In addition, possible modulatory effects of the MCH KO on the long term effects of Ola, i.e. increased adiposity, body weight gain, have not been investigated yet.

SU86 - VALIDATION STUDY IN TWO GENOME-WIDE SIGNIFICANT RISK VARIANTS FOR ANTIPSYCHOTIC INDUCED WEIGHT GAIN

Background Antipsychotic drugs are the primary intervention in the treatment of psychotic disorders, however, the use of antipsychotics is often accompanied by weight gain and metabolic syndrome. A recent Genome-Wide Association Study (GWAS) investigating a Han Chinese sample suggested a possible role of rs1097714 and rs10977154 variants of the protein tyrosine phosphatase, receptor type D (PTPRD) gene in antipsychotic induced weight gain (AIWG). Additionally, two upstream variants (rs1886243 and rs6915627) of T-complex 11 (TCP11) were among the 20 most significant SNPs in the original study. The purpose of this study was to replicate the association of the top 20 variants from the aforementioned GWAS in two independent samples to evaluate whether these associations are also present in patients of European and African American ancestry. Methods The following two independent samples were used: 1) schizophrenia or schizoaffective disorder patients (based on DSM III and DSM IV criteria) primary undergoing first exposure to atypical antipsychotic drugs and 2) patients in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) sample. Samples 1 and 2 were genotyped using Illumina Omni 2.5 Chip, Affymetrix 500 K “A” chipset, and the Perlegen custom 164 K chip, respectively. In the main analyses in two replication samples. Analysis of Covariance (ANCOVA) was used to investigate the percentage of change in weight (Sample 1) or Body Mass Index (BMI) (Sample 2) from baseline to last observation carried forward (LOCF), where genotypes were coded as factors. Models in both samples were corrected for study duration, and additionally for age in Sample 1, and medications used in Sample 2. Results In Sample 1 (122 men (65.9%), mean±SD age; 36±11 years, baseline body weight; 79.72±15.9 kg % of weight change (LOCF); 5.08±7.11, weight gainer (>7%); n=57 (31.0%), medication: clozapine, olanzapine, and risperidone were mainly used), none of 14 genetic variants showed a significant association with % of weight change in the European population. In African Americans, the nominal association was observed (F2,50=4.814; p=0.034) between rs3853114 variant of dynein axonemal heavy chain 5 (DNAH5). In Sample 2 (118 men (78.1%), mean±SD age; 40±12 years, baseline BMI; 28.63±5.43, % of BMI change (LOCF); 2.95±7.79, weight gainer (>7%); n=31 (20.5%), medication: olanzapine, risperidone, and quetiapine were used), nominal associations with two TCP11 variants rs1886243 (F2,148=3.14; p=0.046) and AIWG were observed. None of the variants described above survived correction for multiple testing. Discussion To the best of our knowledge, this is the first genetic association study evaluating PTPRD and TCP11 in European and African American patients. However, the associations between PTPRD variants and AIWG were not replicated; whereas the effects of TCP11 remained nominally significant. More studies across different ancestries are needed to examine if PTPRD and TCP11 can be considered susceptibility genes for AIWG.

Invited talk: Use of a potent calorie restriction mimetic to selectively recover POMC activity, thereby reversing dietary induced weight gain

Invited talk: Use of a potent calorie restriction mimetic to selectively recover POMC activity, thereby reversing dietary induced weight gain

Modeling the Effect of Antipsychotic Drugs on Body Weight of Psychiatric Patients

Various studies have confirmed the significance increase in weight between baselines and follow up after commencement of antipsychotic drugs. Both Atypical Antipsychotic Drugs (AAD) and Typical Antipsychotic Drugs (TAD) have shown the tendency of inducing increase in the fat content of the body. However the modeling of the exact size of the weight increase beyond probable interval estimate is a necessity for clearer understanding; that will foster easy control of weight gain in psychiatric patient. This study thus established the claim from previous studies and presents the odds of AAD inducing weight gain relative to TAD. The study used a composite trinomial and bernoulli distribution to describe the interest variables (IV’s) body mass index (BMI) and the drug type. The composite function parameters and its standard errors were obtained using maximum likelihood estimation (MLE) method and fisher approach respectively. The study further used the continuation ratio model to determine the exact weight gain proportion due to AAD relative to TAD. The study was carried out at the Out-patient clinic of the Federal Neuropsychiatric Hospital Aro, Abeokuta Nigeria, within a period of six weeks between baseline and follow up. A total of two hundred and seventy patients participated in the study after their consent and willingness were obtained. The difficulty to control the food intake of the patient at home is a limitation to the study. Patients that have had reasons to switch were excluded from the study. A graphical representation was used to explain the exact behavioural pattern of the weight gain and its relative effect due to AAD and TAD drugs. The study thus recommends a thorough follow up of healthy eating of food rich in fibers, fruits and vegetables along with indoor or outdoor physical exercises for psychiatric patients mostly on AAD to prevent future cardiovascular related diseases.

A phenotypic Caenorhabditis elegans screen identifies a selective suppressor of antipsychotic-induced hyperphagia

Antipsychotic (AP) drugs are used to treat psychiatric disorders but are associated with significant weight gain and metabolic disease. Increased food intake (hyperphagia) appears to be a driving force by which APs induce weight gain but the mechanisms are poorly understood. Here we report that administration of APs to C. elegans induces hyperphagia by a mechanism that is genetically distinct from basal food intake. We exploit this finding to screen for adjuvant drugs that suppress AP-induced hyperphagia in C. elegans and mice. In mice AP-induced hyperphagia is associated with a unique hypothalamic gene expression signature that is abrogated by adjuvant drug treatment. Genetic analysis of this signature using C. elegans identifies two transcription factors, nhr-25/Nr5a2 and nfyb-1/NFYB to be required for AP-induced hyperphagia. Our study reveals that AP-induced hyperphagia can be selectively suppressed without affecting basal food intake allowing for novel drug discovery strategies to combat AP-induced metabolic side effects.

Jaboticaba peel powder and jaboticaba peel aqueous extract reduces obesity, insulin resistance and hepatic fat accumulation in rats

This study investigated the effects of freeze-dried jaboticaba peel (FJP) and jaboticaba tea (JE) on obesity parameters of diet-induced obese rats. Thirty-six male Wistar rats were distributed into six groups: AIN-93 M feed a normal control diet; HFF (obese control) feed a high-fat and fructose diet; Prevention FJP (P. FJP) and Treatment FJP (T. FJP) feed HFF diet with 2% of FJP powder, for 12 and 6 weeks respectively; Prevention JE (P. JE) and Treatment JE (T. JE) were feed with HFF diet and the water was substituted by JE, for 12 and 6 weeks, respectively. Lipid profile, glucose, adiponectin and leptin were measured. Glucose and insulin tolerance, also pancreatic islet insulin secretion were determined. Liver morphology and fat liver accumulation were evaluated. Results showed that HFF-diet induced weight gain, dyslipidemia, glucose intolerance, insulin resistance and hepatic steatosis. All FJP and JE treatments reduced weight gain, adiposity and improved insulin sensitivity. Twelve weeks supplementation increased HDL-cholesterol and prevented hepatic steatosis. Our results suggest that FJP and JE act as functional foods, being a dietary strategy to prevent or control obesity. FJP and JE 12 weeks supplementation can modulate important parameters of obesity and insulin metabolism, preventing liver steatosis in obese rats.

Sesaminol diglucoside, a water-soluble lignan from sesame seeds induces brown fat thermogenesis in mice

Brown adipose tissue (BAT) is the site of non-shivering thermogenesis in mammals, wherein energy is dissipated as heat. We observed that aqueous extract of black sesame seed triggers an increase in the expression of Uncoupling Protein 1 (UCP1) in brown adipocytes from mice. The active component from the extract was purified and identified to be sesaminol diglucoside (SDG). SDG treatment decreased mass of white fat pads and serum glucose levels and increased UCP1 levels in BAT thereby protecting mice against high fat induced weight gain. Further in silico and in vitro studies revealed that these effects are due to the agonist like behaviour of SDG towards beta 3 adrenergic receptors (β3-AR). Together, our results suggest that SDG induces BAT mediated thermogenesis through β3-AR and protects mice against diet-induced obesity.

Gold nanoparticles as cell regulators: beneficial effects of gold nanoparticles on the metabolic profile of mice with pre-existing obesity

BackgroundWe have previously shown that intraperitoneal injection of gold nanoparticles (AuNPs, 20–30 nm) into mice, decreases high-fat diet (HFD) induced weight gain and glucose intolerance, via suppression of inflammatory responses in both fat and liver tissues. This study investigates whether AuNPs provide similar benefit to mice with pre-existing obesity. Male C57BL/6 mice were fed a HFD for 15 weeks. AuNPs (OB-EAu 0.0785 μg/g/day, OB-LAu 0.785 μg/g/day, OB-HAu7.85 μg/g/day, ip) were administered to subgroups of HFD-fed mice over the last 5 weeks. Control group was fed standard chow and administered vehicle injection.ResultsOnly the OB-LAu group demonstrated significant weight loss (12%), while all AuNP treated groups showed improved glycaemic control and reduced blood lipid levels. In the fat tissue, mRNA expression of pro-inflammatory markers were unchanged following AuNP treatment, while glucose and lipid metabolic markers were improved in OB-LAu and OB-HAu mice. In the liver, AuNP treatment downregulated inflammatory markers and improved lipid metabolic markers, with marked effects in OB-EAu and OB-LAu groups.ConclusionsAuNP treatment can improve glucose and fat metabolism in mice with long-term obesity, however weight loss was only observed in a single specific dose regime. AuNP therapy is a promising new technology for managing metabolic disorders in the obese.

Abstract P193: Angiotensin-(1-7) Acutely Induces Browning of White Adipose Tissue in Mice

Angiotensin (Ang)-(1-7) is a beneficial hormone of the renin-angiotensin system that is emerging as a promising target for obesity. We previously showed that chronic Ang-(1-7) treatment attenuates high fat diet (HFD)-induced weight gain in mice by increasing markers of thermogenesis in subcutaneous white adipose tissue (“browning”) to increase energy expenditure. In this study, we tested the hypothesis that Ang-(1-7) could acutely increase adipose thermogenesis in mice. To test this, adult male C57BL/6J mice were placed on a chow diet or 60% HFD for 12 weeks and then received a single subcutaneous injection of Ang-(1-7) (2mg/kg) or saline. This study included 4 groups of mice: chow+saline (n=9), chow+Ang-(1-7) (n=15), HFD+saline (n=8), HFD+Ang-(1-7) (n=10). Core temperature was measured at baseline and at 6 hours after injection. Subcutaneous white and brown adipose tissues were collected 6 hours post-injection. Gene expression of the thermogenic marker uncoupling protein 1 (UCP1) was measured in tissues by quantitative real-time PCR and quantified with 2-ΔΔCT methods. Acutely, Ang-(1-7) did not alter body mass in chow or HFD mice ( P= 0.992). There were 5 chow fed mice (33%) and 2 HFD mice (20%) that did not respond to Ang-(1-7) injection. In the chow diet responders, Ang-(1-7) increased core temperature (36.7±0.2 vs 35.9±0.2°C saline; P =0.012) and UCP1 gene expression in subcutaneous white adipose tissue (14.3±5.8 vs 1.9±0.6 saline; P =0.050), with no effect in brown adipose tissue (1.7±0.6 vs 1.0±0.2 saline, P =0.284). In the HFD responders, core temperature was not altered by Ang-(1-7) (37.8±0.1 vs 37.8±0.1 saline, P =0.689). There was a trend towards decreased UCP1 expression in white adipose of HFD-saline mice compared to chow-saline mice ( P =0.196). Ang-(1-7) significantly increased UCP1 expression in subcutaneous white adipose of HFD responders (6.2±3.1 vs 0.9±0.2 saline, P =0.036), with no effect in brown adipose tissue (1.2±0.1 vs saline: 1.7±0.4 saline, P =0.402). These data provide further evidence that targeting Ang-(1-7) may be a promising strategy to increase white adipose thermogenesis, an effect that could serve to enhance energy expenditure and restore energy balance in obesity.

Glucocorticoid-induced insulin resistance is related to macrophage visceral adipose tissue infiltration

Insulin resistance is frequently present in patients with glucocorticoid (GC) excess (Cushing’s syndrome) or treated with high doses of GCs. Furthermore, others similarities between metabolic syndrome (visceral obesity, elevated blood glucose levels, dyslipidemia) and Cushing’s syndrome suggest that GCs could play a role in obesity-linked complications. Here we reported that long-term corticosterone (CORT) exposure in mice induced weight gain, dyslipidemia as well as hyperglycaemia and systemic insulin resistance. CORT-treated mice exhibited an increased 11β-Hsd1 expression and corticosterone levels in fat depots but a specific upregulation of glucocorticoid receptor (Gr) and hexose-6-phosphate dehydrogenase only in gonadal adipose tissue, suggesting that GC could act differentially on various fat depots. Despite fat accumulation in all depots, an increased expression of adipogenic (Pparγ, C/ebpα) and lipogenic (Acc, Fas) key genes was restricted to gonadal adipose tissue. Hypertrophied adipocytes observed in both visceral and subcutaneous depots also resulted from reduced lipolytic activity due to CORT treatment. Surprisingly, GC treatment promoted macrophage infiltration (F4/80, Cd68) within all adipose tissues along with predominant M2-like macrophage phenotype, and can directly act on macrophages to induce this phenotype. Moreover, macrophage infiltration preceded mass gain and adipocyte hypertrophy. Of note, specific macrophage depletion in gonadal fat preferentially reduced the M2-like macrophage content, and partially restored insulin sensitivity in mice with GC-induced obesity and insulin resistance. These data provide evidence that GCs act on adipose tissue in a depot-dependent manner and that gonadal adipose macrophages are key effectors of GC-associated insulin resistance.

Deciphering the Roles of PPARγ in Adipocytes via Dynamic Change of Transcription Complex.

Peroxisome proliferator-activated receptor γ (PPARγ), a ligand-dependent transcription factor highly expressed in adipocytes, is a master regulator of adipogenesis and lipid storage, a central player in thermogenesis and an active modulator of lipid metabolism and insulin sensitivity. As a nuclear receptor governing numerous target genes, its specific signaling transduction relies on elegant transcriptional and post-translational regulations. Notably, in response to different metabolic stimuli, PPARγ recruits various cofactors and forms distinct transcriptional complexes that change dynamically in components and epigenetic modification to ensure specific signal transduction. Clinically, PPARγ activation via its full agonists, thiazolidinediones, has been shown to improve insulin sensitivity and induce browning of white fat, while undesirably induce weight gain, visceral obesity and other adverse effects. Thus, deciphering the combinatorial interactions between PPARγ and its transcriptional partners and their preferential regulatory network in the processes of development, function and senescence of adipocytes would provide us the molecular basis for developing novel partial agonists that promote benefits of PPARγ signaling without detrimental side effects. In this review, we discuss the dynamic components and precise regulatory mechanisms of the PPARγ-cofactors complexes in adipocytes, as well as perspectives in treating metabolic diseases via specific PPARγ signaling.

Loss of HDAC6 alters gut microbiota and worsens obesity.

Alterations in gut microbiota are known to affect intestinal inflammation and obesity. Antibiotic treatment can affect weight gain by elimination of histone deacetylase (HDAC) inhibitor-producing microbes, which are anti-inflammatory by augmenting regulatory T (Treg) cells. We asked whether mice that lack HDAC6 and have potent suppressive Treg cells are protected from microbiota-induced accelerated weight gain. We crossed wild-type and HDAC6-deficient mice and subjected the offspring to perinatal penicillin, inducing weight gain via microbiota disturbance. We observed that male HDAC6-deficient mice were not protected and developed profoundly accelerated weight gain. The antibiotic-exposed HDAC6-deficient mice showed a mixed immune phenotype with increased CD4+ and CD8+ T-cell activation yet maintained the enhanced Treg cell-suppressive function phenotype characteristic of HDAC6-deficient mice. 16S rRNA sequencing of mouse fecal samples reveals that their microbiota diverged with time, with HDAC6 deletion altering microbiome composition. On a high-fat diet, HDAC6-deficient mice were depleted in representatives of the S24-7 family and Lactobacillus but enriched with Bacteroides and Parabacteroides; these changes are associated with obesity. Our findings further our understanding of the influence of HDACs on microbiome composition and are important for the development of HDAC6 inhibitors in the treatment of human diseases.-Lieber, A. D., Beier, U. H., Xiao, H., Wilkins, B. J., Jiao, J., Li, X. S., Schugar, R. C., Strauch, C. M., Wang, Z., Brown, J. M., Hazen, S. L., Bokulich, N. A., Ruggles, K. V., Akimova, T., Hancock, W. W., Blaser, M. J. Loss of HDAC6 alters gut microbiota and worsens obesity.

The structure of human Nocturnin reveals a conserved ribonuclease domain that represses target transcript translation and abundance in cells.

The circadian protein Nocturnin (NOCT) belongs to the exonuclease, endonuclease and phosphatase superfamily and is most similar to the CCR4-class of deadenylases that degrade the poly-adenosine tails of mRNAs. NOCT-deficient mice are resistant to high-fat diet induced weight gain, and exhibit dysregulation of bone formation. However, the mechanisms by which NOCT regulates these processes remain to be determined. Here, we describe a pair of high-resolution crystal structures of the human NOCT catalytic domain. The active site of NOCT is highly conserved with other exoribonucleases, and when directed to a transcript in cells, NOCT can reduce translation and abundance of that mRNA in a manner dependent on key active site residues. In contrast to the related deadenylase CNOT6L, purified recombinant NOCT lacks in vitro ribonuclease activity, suggesting that unidentified factors are necessary for enzymatic activity. We also find the ability of NOCT to repress reporter mRNAs in cells depends upon the 3′ end of the mRNA, as reporters terminating with a 3′ MALAT1 structure cannot be repressed by NOCT. Together, these data demonstrate that NOCT is an exoribonuclease that can degrade mRNAs to inhibit protein expression, suggesting a molecular mechanism for its regulatory role in lipid metabolism and bone development.

A role of neuropeptide CART in hyperphagia and weight gain induced by olanzapine treatment in rats

Although olanzapine is highly efficacious and most widely used second generation antipsychotic drug, the success of treatment has been hampered by its propensity to induce weight gain. While the underlying neuronal mechanisms are unclear, their elucidation may help to target alternative pathways regulating energy balance. The present study was undertaken to define the role of cocaine- and amphetamine-regulated transcript (CART), a well-known anorexic peptide, in olanzapine-induced hyperphagia and body weight gain in female rats. Olanzapine was administered daily by intraperitoneal route, alone or in combination with CART (intracerebroventricular) for a period of two weeks. Immediately after drug administrations, preweighed food was offered to the animals at the commencement of the dark phase. The food intake and body weight were measured daily just prior to next injection. Furthermore, the brains of olanzapine-treated rats were processed for the immunohistochemical analysis of CART-containing elements in the hypothalamus. Treatment with olanzapine (0.5 mg/kg) for the duration of 14 days produced a significant increase in food intake and body weight as compared to control. However, concomitant administration of CART (0.5 µg) attenuated the olanzapine-induced hyperphagia and weight gain. Olanzapine administration resulted in a significant reduction in CART immunoreactivity in the hypothalamic arcuate, paraventricular, dorsomedial and ventromedial nuclei. We suggest that decreased CART contents in the hypothalamus may be causally linked with the hyperphagia and weight gain induced by olanzapine.

Cannabinoid receptor 1 blockade attenuates metabolic inflammation and gut microbial dysbiosis during high-fat diet-induced obesity.

Abstract The endocannabinoid (eCB) system regulates a variety of physiological processes including inflammation and metabolism. Obesity is characterized by overactivation of the eCB system, chronic low-grade inflammation, metabolic dysfunction, and gut microbial dysbiosis. Blockade of cannabinoid receptor 1 (CB1) ameliorates obesity, however CB1-mediated immune-microbial interactions have not been extensively explored. In the current study, antagonists and genetic ablation of CB1 were used in a mouse model of diet-induced obesity to determine the role of CB1 in modulating inflammation, metabolism, and the gut microbiome. As expected, CB1−/− mice were resistant to high-fat diet (HFD)-induced weight gain and metabolic inflammation was significantly less in CB1−/− mice when compared to wild-type (WT) controls. Lamina propria lymphocytes from CB1−/− mice did not display a Th1 induction after HFD feeding whereas WT mice fed HFD had elevated CD4+T-bet+ cells compared to WT mice fed low-fat diet. Decreased colonic inflammation indicated CB1-dependent alterations in the gut microbiome may contribute to a decreased obese phenotype. Similarly, WT obese mice treated with the CB1 antagonist AM251 experienced weight loss, decreased inflammation, and improvement in metabolic parameters. Interrogation of the gut microbiome by 16S metagenomics revealed CB1-dependent alterations in abundance of bacteria belonging to the Clostridiales order. In addition, functional predictions by PICRUSt analysis revealed decreased abundance of operational taxonomic units belonging to bacterial metabolism and membrane transport pathways. Together these data suggest CB1 regulates metabolism by shaping the immune response and gut microbial community.

Experimental Weight Gain Increases Ambulatory Blood Pressure in Healthy Subjects: Implications of Visceral Fat Accumulation

ObjectiveTo examine whether experimentally induced weight gain raises ambulatory blood pressure (BP) in healthy subjects and identify any relationship between changes in BP and changes in regional fat distribution. Patients and MethodsTwenty-six normal weight subjects were randomized to 8 weeks of weight gain through overfeeding (n=16; age, 30.4±6.6 years) or to weight maintenance (controls; n=10; age, 27.1±7.7 years) between July 2004 and August 2010. Measures of body composition via dual energy X-ray absorptiometry and computed tomography, circulating biomarkers, and 24-hour ambulatory BP were obtained at baseline and after the 8-week experimental phase. ResultsOverfeeding resulted in 3.7 kg (95% CI, 2.9-4.5) increase in body weight in weight gainers, with increments in total (46.2 cm2; 95% CI, 27.6-64.9), visceral (13.8 cm2; 95% CI, 5.8-21.9), and subcutaneous fat (32.4 cm2; 95% CI, 13.5-51.3). No changes occurred in the maintenance group. Increases in 24-hour systolic BP (4 mm Hg; 95% CI, 1.6-6.3), mean BP (1.7 mm Hg; 95% CI, 0.3-3.3), and pulse pressure (2.8 mm Hg; 95% CI, 1.1-4.4) were evident after weight gain in the experimental group, whereas BP remained unchanged in controls. Changes in mean BP correlated only with changes in visceral fat (ρ=0.45; P=.02), but not with changes in other body composition measures. ConclusionModest weight gain causes elevation in 24-hour BP in healthy subjects. The association between increased BP and abdominal visceral fat accumulation suggests that visceral deposition of adipose tissue may contribute specifically to the enhanced risk of hypertension associated with weight gain.

Reversal of Diabetic Stem/progenitor Cell Mobilopathy by a Nonapeptide Antagonist of Leptin Receptor

Adult bone marrow‐derived hematopoietic stem/progenitor cells (HSPCs) have the propensity of re‐endothelialization and revascularization following ischemic vascular damage. Diabetes is associated with severe impairment in pharmacological mobilization of HSPCs by granulocyte‐colony stimulating factor (G‐CSF) or plerixafor. Leptin, an adipocyte‐derived hormone, elicits pro‐hematopoietic functions by acting on leptin receptor (LepR). LepR is expressed in HSPCs. We have previously reported that leptin‐LepR pathway negatively modulates HSPC mobilization by G‐CSF or plerixafor, and that LepR‐antagonist, PESLAN‐1 exacerbated G‐CSF‐ or plerixafor‐induced mobilization. However, LepR‐antagonism is known to increase the food intake and body weight. In this study we tested the efficacy of a nonapeptide antagonist of LepR, allo‐aca, which cannot cross the blood brain barrier, in reversing the diabetic mobilization dysfunction. The study was performed in age‐matched control and streptozotocin (STZ)‐induced diabetic mice (C57Bl/6). Mobilization induced by G‐CSF (125 μg/Kg, s.c., twice a day, 4 days) or plerixafor (5 mg/Kg, s.c., single dose) was evaluated by flow‐cytometric enumeration of circulating Lineage−Sca‐1+cKit+ (LSK) cells, and by colony forming unit (CFU) assay. Effects of allo‐aca (0.3 mg/Kg/day, s.c., 28 days) (Peptides International) or PESLAN‐1 (10 mg/Kg, s.c., once in two days for 18 days) were evaluated on body weight, basal/mobilized levels of LSK cells and CFUs. No significant change in body weight was observed in control or diabetic mice treated with allo‐aca, in contrast PESLAN‐1 caused gradual increase in body weight of control mice (14% vs untreated control, P<0.01). In control mice (n=7), allo‐aca treatment has no effect on basal mobilization of LSK cells but it robustly potentiated G‐CSF‐ or plerixafor‐induced mobilization of LSK cells (6.39±1.05‐ and 1.39±0.1‐fold higher (P<0.05), respectively, than untreated). Along similar lines, pretreatment with PESLAN‐1 potentiated LSK mobilization by G‐CSF (n=7, P<0.001) or plerixafor (n=6, P<0.05). In agreement with our previous findings, LSK mobilization was impaired in response to G‐CSF‐ or plerixafor (n=6 to 8, P<0.01 vs control) in diabetic mice, which was reversed by allo‐aca treatment (8.05±1.83‐ and 6.68±1.16‐fold higher (n=7, P<0.05), respectively, than untreated). Consistent with flow cytometric enumeration, CFUs derived from G‐CSF‐mobilized cells were decreased in STZ‐diabetic mice compared to control (n=6 to 8, P<0.05 vs control) and treatment with allo‐aca increased CFUs in the circulating cells in diabetic mice in response to G‐CSF (n=6, P< 0.05 vs allo‐aca untreated). Collectively, these results suggest that the novel nonapeptide‐antagonist of LepR, allo‐aca, is a promising molecule for reversing diabetic HSPC mobilopathy without inducing weight gain.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Tpcn2 Knock‐Out Mice Have Improved Insulin Sensitivity and Are Protected Against High‐Fat Diet Induced Weight Gain.

Type 2 diabetes is a complex disorder affected by multiple genes and the environment. Our laboratory has shown that in response to a glucose challenge, two‐pore channel 2 (Tpcn2) knock‐out mice exhibit a decreased insulin response but normal glucose clearance, suggesting they have improved insulin sensitivity compared to wild type mice. We tested the hypothesis that improved insulin sensitivity inTpcn2 knock‐out mice would protect against the negative effects of a high fat diet. Male and female Tpcn2 knock‐out (KO), heterozygous (Het) and wild‐type (WT) mice were fed a low fat (LF) or high fat (HF) diet for 24 weeks. HF diet significantly increases body weight in WT mice relative to those on the LF diet, whereas HF diet consumption does not significantly affect body weight in Het or KO mice. We confirm that male KO mice have improved insulin sensitivity relative to WT mice. Unfortunately, because HF diet does not lead to insulin resistance in any of the mice, we are unable to claim a direct relationship between diet‐induced protection from insulin resistance and weight gain in the KO mice. Male KO mice exhibit increased fasting plasma total cholesterol and triglyceride concentrations relative to WT mice on the LF diet, but this difference disappears in HF diet‐fed mice where there is increased cholesterol and triglycerides across all genotypes. Fasting glucose, insulin and glucose tolerance levels do not differ by genotype or diet in male mice. In contrast, females consuming the HF diet exhibit glucose intolerance and hyperinsulinemia relative to females on the LF diet, but these effects are independent of genotype. These data demonstrate that male KO mice have improved insulin sensitivity and both male and female KO mice are protected against diet‐induced weight gain independent from changes in glucose tolerance or lipid levels.Support or Funding Informationby R01 DK088975, R01 DK106386, Department of Pediatrics at the Medical College of WisconsinThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.