Diet-induced Obese Male Rats Research Articles

Paternal high-fat diet affects weight and DNA methylation of their offspring

Obesity poses a public health threat, reaching epidemic proportions. Our hypothesis suggests that some of this epidemic stems from its transmission across generations via paternal epigenetic mechanisms. To investigate this possibility, we focused on examining the paternal transmission of CpG methylation. First-generation male Wistar rats were fed either a high-fat diet (HF) or chow and were mated with females fed chow. We collected sperm from these males. The resulting offspring were raised on a chow diet until day 35, after which they underwent a dietary challenge. Diet-induced obese (DIO) male rats passed on the obesogenic trait to both male and female offspring. We observed significant hypermethylation of the Pomc promoter in the sperm of HF-treated males and in the hypothalamic arcuate nucleus (Arc) of their offspring at weaning. However, these differences in Arc methylation decreased later in life. This hypermethylation is correlated with increased expression of DNMT3B. Further investigating genes in the Arc that might be involved in obesogenic transgenerational transmission, using reduced representation bisulfite sequencing (RRBS) we identified 77 differentially methylated regions (DMRs), highlighting pathways associated with neuronal development. These findings support paternal CpG methylation as a mechanism for transmitting obesogenic traits across generations.

Preconceptional paternal caloric restriction of high-fat diet-induced obesity in Wistar rats dysregulates the metabolism of their offspring via AMPK/SIRT1 pathway

BackgroundObesity is a metabolic syndrome where allelic and environmental variations together determine the susceptibility of an individual to the disease. Caloric restriction (CR) is a nutritional dietary strategy recognized to be beneficial as a weight loss regime in obese individuals. Preconceptional parental CR is proven to have detrimental effects on the health and development of their offspring. As yet studies on maternal CR effect on their offspring are well established but paternal CR studies are not progressing. In current study, the impact of different paternal CR regimes in diet-induced obese male Wistar rats (WNIN), on their offspring concerning metabolic syndrome are addressed.MethodsHigh-fat diet-induced obese male Wistar rats were subjected to caloric restriction of 50% (HFCR-I) and 40% (HFCR-II) and then they were mated with normal females. The male parent’s reproductive function was assessed by sperm parameters and their DNMT’s mRNA expression levels were also examined. The offspring’s metabolic function was assessed by physiological, biochemical and molecular parameters.ResultsThe HFCR-I male parents have shown reduced body weights, compromised male fertility and reduced DNA methylation activity. Further, the HFCR-I offspring showed attenuation of the AMPK/SIRT1 pathway, which is associated with the progression of proinflammatory status and oxidative stress. In line, the HFCR-I offspring also developed altered glucose and lipid homeostasis by exhibiting impaired glucose tolerance & insulin sensitivity, dyslipidemia and steatosis. However, these effects were largely mitigated in HFCR-II offspring. Regarding the obesogenic effects, female offspring exhibited greater susceptibility than male offspring, suggesting that females are more prone to the influences of the paternal diet.ConclusionThe findings highlight that HFCR-I resulted in paternal undernutrition, impacting the health of offspring, whereas HFCR-II largely restored the effects of a high-fat diet on their offspring. As a result, moderate caloric restriction has emerged as an effective weight loss strategy with minimal implications on future generations. This underscores the shared responsibility of fathers in contributing to sperm-specific epigenetic imprints that influence the health of adult offspring.

Reductions of food intake and body weight in diet-induced obese rats following chronic treatment with a monomeric peptide multiagonist

While therapies based on endogenous gut peptides such as glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) have been compelling therapeutic agents for obesity and type 2 diabetes (T2D), only a few have achieved long-term weight loss and all have shown significant side-effects, including nausea/malaise and gastrointestinal ailments. As the pathophysiology of obesity is driven by dysregulation of multiple, inter-related, pathways, we tested a novel peptide targeting multiple receptors of complementary neurocircuits regulating the controls of energy balance. Response to daily injections of GEP44, a GLP-1R and neuropeptide Y1R and Y2R receptor (Y1R/Y2R) triple agonist was tested vs. the GLP-1R agonist liraglutide (LIRA) in diet-induced obese (DIO) male and female rats. Glucose tolerance tests after intraperitoneal injection of glucose (IPGTT) were performed at baseline and after 14-d of treatment in GEP44 treated rats. Other metabolic parameters were assessed in blood at the end of a 28-d intervention. Upon conclusion at 28-d, body weight reduction compared to vehicle was-15.6%/-11.9% in response to GEP44, vs.-9.7%/-5.1% after LIRA, males, and females, respectively. Significant reductions of cumulative food intake occurred over 28-d in female rats treated with GEP44 (-30%; p<0.0001), vs. LIRA (-10%), and in male rats GEP44 (-39%; p<0.0001), vs. LIRA (-20%; p=0.003). In IPGTTs, a similar stimulation glucose induced insulin secretion was noted in rats treated with GEP44 and LIRA. The strong reductions of body weight in response to long-term applications of the triple agonist GEP44 confirms the therapeutic potential of targeting multiple receptors for achieving more robust and potentially more sustained improvement of energy balance.

Effects of NPY-2 Receptor Antagonists, Semaglutide, PYY3-36, and Empagliflozin on Early MASLD in Diet-Induced Obese Rats.

(1) Background: Modulators of the Neuropeptide Y (NPY) system are involved in energy metabolism, but the effect of NPY receptor antagonists on metabolic-dysfunction-associated steatotic liver disease (MASLD), a common obesity-related comorbidity, are largely unknown. In this study, we report on the effects of antagonists of the NPY-2 receptor (Y2R) in comparison with empagliflozin and semaglutide, substances that are known to be beneficial in MASLD. (2) Methods: Diet-induced obese (DIO) male Wistar rats were randomized into the following treatment groups: empagliflozin, semaglutide ± PYY3-36, the Y2R antagonists JNJ 31020028 and a food-restricted group, as well as a control group. After a treatment period of 8 weeks, livers were weighed and histologically evaluated. QrtPCR was performed to investigate liver inflammation and de novo lipogenesis (in liver and adipose tissue). Serum samples were analysed for metabolic parameters. (3) Results: Semaglutide + PYY3-36 led to significant weight loss, reduced liver steatosis (p = 0.05), and decreased inflammation, insulin resistance, and leptin levels. JNJ-31020028 prevented steatosis (p = 0.03) without significant weight loss. Hepatic downregulation of de novo lipogenesis-regulating genes (SREBP1 and MLXIPL) was observed in JNJ-31020028-treated rats (p ≤ 0.0001). Food restriction also resulted in significantly reduced weight, steatosis, and hepatic de novo lipogenesis. (4) Conclusions: Body weight reduction (e.g., by food restriction or drugs like semaglutide ± PYY3-36) is effective in improving liver steatosis in DIO rats. Remarkably, the body-weight-neutral Y2R antagonists may be effective in preventing liver steatosis through a reduction in de novo lipogenesis, making this drug class a candidate for the treatment of (early) MASLD.

Effect of treadmill exercise on the liver, kidney health, and serum IL-10 levels in high-fat diet-induced obese male Wistar rats

This study investigated the impact of treadmill exercise on liver and kidney health in obese rats induced by a high-fat diet (HFD), alongside serum IL-10 levels. Rats were divided into normal control, HFD, HFD with atorvastatin, and HFD with exercise groups. Obesity was induced over 11 months via the HFD, while the exercise group underwent treadmill training three times per week for 90 days. Parameters measured included body weight, lipid profile, liver and kidney function tests, rat interleukine-10, and histopathology of the liver and kidney. Significant increases in body weight, lipid profile, and liver and kidney function tests, alongside decreased IL-10 levels, were observed in the HFD groups, indicating obesity-associated complications. After 90 days of exercise, significant reductions in body weight and lipid profile, alongside improved liver and kidney functions were noted, accompanied by increased IL-10 expression. The exercise group exhibited occasional liver micro vesicular fat droplets but an otherwise healthy liver and kidney appearance. Treadmill exercise demonstrated beneficial effects on liver and kidney health in male obese rats with HFD-induced obesity, primarily through the amelioration of IL-10 levels.

Oleaster oil (Olea europaea sylvestris) effects on the efficiency of the reproductive system of diet-induced obese male Wistar rats

Abstract Objectives Obesity is the result of oxidative stress (OS), which appears to be linked to male infertility. Oleaster oil has multiple therapeutic virtues due to its richness in natural bioactive compounds. This study aimed to evaluate the effect of Algerian oleaster oil on the reproductive system effectiveness of diet-induced obese male Wistar rats. Methods The oil was extracted with an oleodoseur from the oleaster fruits. Rats were fed for 28 weeks two diets: a normal diet (NC group, n=8) and a high-fat, high-sucrose diet (HFHS group, n=32). The obese rats in the HFHS group were then split into three groups at random: the HFHS group, which continued to receive the HFHS diet; the HFHS L-OO group; and the HFHS H-OO group, which received for 6 weeks, respectively, in combination with the HFHS diet, oleaster oil at 1.5 and 3 mL/100 g body weight (BW). Then, the animals were sacrificed. Semen and testes were removed for semen analysis, OS, and histopathological evaluation. Results The oleaster oil diet induces an improvement in sperm count and viability and a decrease in the percentage of fragmented sperm DNA compared to the group fed the HFHS diet, preserving the testes against OS with a highly significant decrease in testicular MDA. This beneficial effect of oleaster oil on the reproductive efficiency of rats fed the HFHS diet was dose-dependent. Conclusions The results showed that the oil decreased body weight, prevented OS and improved male reproductive indicators in HFHS-fed animals. The potential positive effects of oleaster oil on fertility biomarkers may be attributed to its ability to mitigate OS.

Hypoabsorptive surgeries cause limb-dependent changes in the gut endocannabinoidome and microbiome in association with beneficial metabolic effects.

To determine whether the metabolic benefits of hypoabsorptive surgeries are associated with changes in the gut endocannabinoidome (eCBome) and microbiome. Biliopancreatic diversion with duodenal switch (BPD-DS) and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) were performed in diet-induced obese (DIO) male Wistar rats. Control groups fed a high-fat diet (HF) included sham-operated (SHAM HF) and SHAM HF-pair-weighed to BPD-DS (SHAM HF-PW). Body weight, fat mass gain, fecal energy loss, HOMA-IR, and gut-secreted hormone levels were measured. The levels of eCBome lipid mediators and prostaglandins were quantified in different intestinal segments by LC-MS/MS, while expression levels of genes encoding eCBome metabolic enzymes and receptors were determined by RT-qPCR. Metataxonomic (16S rRNA) analysis was performed on residual distal jejunum, proximal jejunum, and ileum contents. BPD-DS and SADI-S reduced fat gain and HOMA-IR, while increasing glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) levels in HF-fed rats. Both surgeries induced potent limb-dependent alterations in eCBome mediators and in gut microbial ecology. In response to BPD-DS and SADI-S, changes in gut microbiota were significantly correlated with those of eCBome mediators. Principal component analyses revealed connections between PYY, N-oleoylethanolamine (OEA), N-linoleoylethanolamine (LEA), Clostridium, and Enterobacteriaceae_g_2 in the proximal and distal jejunum and in the ileum. BPD-DS and SADI-S caused limb-dependent changes in the gut eCBome and microbiome. The present results indicate that these variables could significantly influence the beneficial metabolic outcome of hypoabsorptive bariatric surgeries.

Impact of Calorie-Restricted Cafeteria Diet and Treadmill Exercise on Sweet Taste in Diet-Induced Obese Female and Male Rats

The goal of the present study was to evaluate the sweet taste function in obese rats fed with a 30% calorie-restricted cafeteria diet (CAFR) and/or subjected to moderate treadmill exercise (12-17 m/min, 35 min, 5 days per week) for 9 weeks. A two-bottle preference test, a taste reactivity test, and a brief-access licking test were carried out when animals were aged 21 weeks; biometric and metabolic parameters were also measured along the interventions. Two separate experiments for females and males were performed. Behaviorally, CAF diet decreased sucrose intake and preference, as well as perceived palatability, in both sexes and decreased hedonic responses in males. Compared to the CAF diet, CAFR exerted a corrective effect on sweet taste variables in females by increasing sucrose intake in the preference test and licking responses, while exercise decreased sucrose intake in both sexes and licking responses in females. As expected, CAF diet increased body weight and Lee index and worsened the metabolic profile in both sexes, whereas CAFR diet ameliorated these effects mainly in females. Exercise had no noticeable effects on these parameters. We conclude that CAF diet might diminish appetitive behavior toward sucrose in both sexes, and that this effect could be partially reverted by CAFR diet in females only, while exercise might exert protective effects against overconsumption of sucrose in both sexes.

Histological Study on The Effects of Orlistat on Left Ventricular Myocardium of High Fat Diet-Fed Adult Male Wistar Rats

Obesity-induced by a high-fat diet in animal studies recapitulates the human form of obesity. Obesity is a serious public health concern, a risk factor for many diseases, including cardiovascular disorders. Our study evaluated the impact of orlistat on the left ventricular myocardium in high fat diet-induced obese adult Wistar rats. Our study included fifteen adult male Wistar rats weighing between (130-150g). The rats following environmental acclimatization were assigned into three groups A-C (n=5 each), the control (standard rat diet), high-fat diet only, high-fat diet, and orlistat as A, B, and C, respectively. The rats were placed on diets for eight weeks, which performed the sacrifice and histological procedures. The heart and left ventricles were excised and fixed in 10% buffered formalin solution for histological studies. Body Mass Index (BMI) of the high-fat diet-only group markedly increased (P&lt;0.05) relative to the control and the orlistat-treated groups. Heart weight and relative heart weights were not significantly different across the groups. Histological examination of the left ventricular myocardium with the hematoxylin and eosin stain revealed significant deviation from the regular pattern in the high-fat diet-only group. The orlistat-treated group showed a near-normal left ventricular myocardial histoarchitectural pattern. Orlistat ameliorated left ventricular myocardial alteration, restored elastic tissue component, and reversed increased collagen deposition in high fat diet-induced obese male Wistar rats.

Dietary Intervention Associated With Moderate-Intensity Continuous Training Leads to Changes in the Inflammatory Profile in Visceral Adipose Tissue but Not in Skeletal Muscle in Diet-Induced Obese Rats.

This study aimed to determine the concentrations of inflammatory markers in visceral adipose tissue (VAT) and skeletal muscle, and changes in body mass and adipocyte size in diet-induced obese rats after moderate-intensity continuous training (MICT) and/or dietary intervention. After 8 weeks of obesity induction through a high-fat diet (HFD) consumption, twenty diet-induced obese male Wistar rats were divided into four groups as follows: (i) control rats fed with HFD (HFD-SED), (ii) obese rats fed with HFD and submitted to MICT (HFD-MICT), (iii) obese rats that were submitted to a nutritional intervention by switching HFD to chow diet (CD-SED), and (iv) obese rats that were submitted to MICT and nutritional intervention (CD-MICT). All the animals in the training groups were submitted to MICT, with an intensity of 50–85% of Vmax, 60 min/day, 3 days/week for 8 weeks. Gastrocnemius muscle (GAST) and mesenteric adipose tissue (mWAT) were collected to quantify tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and IL-10 using ELISA. The body mass was recorded before and after the experimental protocols, and the adipocyte morphology was assessed using histological analysis. The results showed that HFD-SED had higher body mass, higher concentrations of inflammatory markers in mWAT, and higher increase in adipocyte size. The CD-SED and CD-MICT groups presented with reduced body mass, relative weight of mWAT, and adipocyte size. Moreover, the inflammatory markers in mWAT were reduced after dietary intervention (TNF-α), MICT (IL-10 and TNF-α), or both interventions combined (IL-6 and TNF-α). In contrast, there was no reduction in GAST-relative weight or concentrations of inflammatory markers for any treatment. Finally, we concluded that 8 weeks of dietary intervention alone and combined with MICT were effective in reducing some of the deleterious effects caused by obesity.

Roux-en-Y Gastric Bypass and Caloric Restriction but Not Gut Hormone-Based Treatments Profoundly Impact the Hypothalamic Transcriptome in Obese Rats.

Background: The hypothalamus is an important brain region for the regulation of energy balance. Roux-en-Y gastric bypass (RYGB) surgery and gut hormone-based treatments are known to reduce body weight, but their effects on hypothalamic gene expression and signaling pathways are poorly studied. Methods: Diet-induced obese male Wistar rats were randomized into the following groups: RYGB, sham operation, sham + body weight-matched (BWM) to the RYGB group, osmotic minipump delivering PYY3-36 (0.1 mg/kg/day), liraglutide s.c. (0.4 mg/kg/day), PYY3-36 + liraglutide, and saline. All groups (except BWM) were kept on a free choice of high- and low-fat diets. Four weeks after interventions, hypothalami were collected for RNA sequencing. Results: While rats in the RYGB, BWM, and PYY3-36 + liraglutide groups had comparable reductions in body weight, only RYGB and BWM treatment had a major impact on hypothalamic gene expression. In these groups, hypothalamic leptin receptor expression as well as the JAK–STAT, PI3K-Akt, and AMPK signaling pathways were upregulated. No significant changes could be detected in PYY3-36 + liraglutide-, liraglutide-, and PYY-treated groups. Conclusions: Despite causing similar body weight changes compared to RYGB and BWM, PYY3-36 + liraglutide treatment does not impact hypothalamic gene expression. Whether this striking difference is favorable or unfavorable to metabolic health in the long term requires further investigation.

Consistent gut bacterial and short-chain fatty acid signatures in hypoabsorptive bariatric surgeries correlate with metabolic benefits in rats.

The study aimed at comparing how changes in the gut microbiota are associated to the beneficial effects of the most clinically efficient hypoabsorptive bariatric procedures, namely Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion with duodenal switch (BPD-DS) and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S). Diet-induced obese (DIO) male Wistar rats were divided into seven groups. In addition to the groups subjected to RYGB, BPD-DS and SADI-S, the following four control groups were included: SHAM-operated rats fed a high-fat diet (SHAM HF), SHAM fed a low-fat diet (SHAM LF), SHAM HF-pair-weighed to BPD-DS (SHAM HF-PW) and sleeve-gastrectomy (SG) rats. Body weight, food intake, glucose tolerance, insulin sensitivity/resistance, and L-cell secretion were assessed. The gut microbiota (16 S ribosomal RNA gene sequencing) as well as the fecal and cæcal contents of short-chain fatty acids (SCFAs) were also analyzed prior to, and after the surgeries. The present study demonstrates the beneficial effect of RYGB, BPD-DS and SADI-S on fat mass gain and glucose metabolism in DIO rats. These benefits were proportional to the effect of the surgeries on food digestibility (BPD-DS > SADI-S > RYGB). Notably, hypoabsorptive surgeries led to consonant microbial signatures characterized by decreased abundance of the Ruminococcaceae (Oscillospira and Ruminococcus), Oscillospiraceae (Oscillibacter) and Christensenellaceae, and increased abundance of the Clostridiaceae (Clostridium), Sutterellaceae (Sutterella) and Enterobacteriaceae. The gut bacteria following hypoabsorptive surgeries were associated with higher fecal levels of propionate, butyrate, isobutyrate and isovalerate. Increases in the fecal SCFAs were in turn positively and strongly correlated with the levels of peptide tyrosine-tyrosine (PYY) and with the beneficial effects of the surgery. The present study emphasizes the consistency with which the three major hypoabsorptive bariatric procedures RYGB, BPD-DS and SADI-S create a gut microbial environment capable of producing a SCFA profile favorable to the secretion of PYY and to beneficial metabolic effects.

Dietary Intervention, When Not Associated With Exercise, Upregulates Irisin/FNDC5 While Reducing Visceral Adiposity Markers in Obese Rats.

Obesity is an epidemic disease and the expansion of adipose tissue, especially visceral fat, promotes the secretion of factors that lead to comorbidities such as diabetes and cardiovascular diseases. Thus, diet and exercise have been proposed as an intervention to reverse these complications. An adipocytokine, known as irisin, mediates the beneficial effects of exercise. It has been proposed as a therapeutic potential in controlling obesity. In view of the above, this paper attempts to determine the modulation of irisin, visceral adiposity and biochemical markers in response to dietary intervention and aerobic exercise. To do this, 52 diet-induced obese male Wistar rats were divided into the following four groups: high-fat diet and exercise (HFD-Ex); HFD-Sedentary (HFD-Sed); chow-diet and exercise (CD-Exercise); and CD-Sed. The exercise-trained group performed a treadmill protocol for 60 min/day, 3 days/week for 8 weeks. Body mass (BM), body fat (BF), fat mass (FM), and fat-free mass (FFM) were analyzed. Mesenteric (MES), epididymal (EPI), and retroperitoneal (RET) adipose tissue was collected and histological analysis was performed. Biochemical irisin, triglycerides, glucose, insulin and inflammatory markers were determined and, FNDC5 protein expression was analyzed. In this study, the diet was the most important factor in reducing visceral adiposity in the short and long term. Exercise was an important factor in preserving muscle mass and reducing visceral depots after a long term. Moreover, the combination of diet and exercise can enhance these effects. Diet and exercise exclusively were the factors capable of increasing the values of irisin/FNDC5, however it did not bring cumulative effects of both interventions. Prescriptions to enhance the obesity treatments should involve reducing visceral adiposity by reducing the fat content in the diet associated with aerobic exercise.

ANTI-OBESITY EFFECTS OF THE METHANOL EXTRACT OF MOMORDICA FOETIDA (CUCURBITACEAE) IN MALE WISTAR RATS

Objective: This study was designed to evaluate the effect of the methanol extract of M. foetida (MEMf) on high fat diet-induced obese male rats.&#x0D; Results: HFD induced an increase (P&lt;0.05) in the body and liver weights and the relative abdominal fat pad of the animals in the experimental groups as compared to those in the normal diet group. Also, HFD in the experimental groups reduced (P&lt;0.05) superoxide dismutase and catalase activities, glutathione levels and increased lipid peroxidation in the liver, heart and kidney as well as altered lipid profile (increased serum triglycerides, total cholesterol, low-density lipoproteins (LDL-C), very low-density lipoproteins (VLDL-C), decreased high-density lipoproteins (HDL-C), increased atherogenic index and coronary risk index), when compared to the normal diet animals. All altered parameters were subsequently normalized when obese rats received either MEMf (50 or100 mg/kg) or the reference drug Atorvastatin.&#x0D; Conclusion: This study demonstrates the potential of MEMf to normalize hyperlipidemia, oxidative stress and animal visceral organ weights increased by HFD in rats. Thus, M. foetida is an interesting medicinal plant that could be exploited as sources of anti-obesity agents.

Sirtuin 1 Regulates Synapsin 1 in POMC-Producing N43-5 Neurons via FOXO1

Abstract The nutrient-sensor protein Sirtuin 1 (Sirt1; silent mating type information regulation 2 homolog 1) has been shown to have significant and opposing effects on insulin resistance, leptin resistance, and body weight in the periphery and the brain. In the hypothalamic arcuate nucleus (ARC) of the brain, Sirt1 increases in the obese state and acts to promote weight gain as well as insulin and leptin resistance by increasing the orexigenic neuropeptides Agouti-related protein (AgRP) and neuropeptide Y (NPY), and in a distinct set of ARC neurons, by decreasing POMC and thus its anorexigenic derivative alpha-melanocyte stimulating hormone (alpha-MSH) (1). Sirt1’s actions on these neuropeptides are mediated at least in part by the deacetylation of the transcription factor forkhead box O1 (FOXO1). Another mechanism by which Sirt1 regulates body weight appears to be through mediating changes in the synapses of these neuropeptide-producing ARC neurons. For example, a previous study demonstrated that Sirt1 inhibition with the specific Sirt1 inhibitor, Ex-527, decreased AgRP-NPY inhibitory synaptic input on POMC neurons, which suggests that the obesity-induced increase in ARC Sirt1 would increase AgRP-NPY inhibition of POMC neurons thus promoting weight gain (2). The present study investigated how Sirt1 regulates synapses specifically in POMC-producing N43-5 neurons. Results reveal that inhibition of Sirt1 with Ex-527 significantly increased the presynaptic marker Synapsin 1 (Syn1) in N43-5 neurons. Furthermore, we investigated whether the Sirt1 target, FOXO1, mediates these synaptic changes. FOXO1 overexpression significantly decreased Syn1 and transfection of mutant FOXO1 significantly increased Syn1. Overall, our results suggest that Sirt1 regulates synapses of POMC neurons and does so in a manner that differs from Sirt1’s regulation of AgRP-NPY neuronal synapses. Future work will elucidate the mechanisms and consequences of Sirt1 and FOXO1 regulation of POMC neuron synapses under different nutritional conditions in vitro and in vivo. (1) Cyr, N. E., Steger, J. S., Toorie, A. M., Yang, J. Z., Stuart, R., Nillni, E. A. (2014). Central Sirt1 Regulates Body Weight and Energy Expenditure Along With the POMC-Derived Peptide α-MSH and the Processing Enzyme CPE Production in Diet-Induced Obese Male Rats, Endocrinology, 155(7), 2423–2435. (2) Dietrich, M. O., Antunes, C., Geliang, G., Liu, Z., Borok, E., Nie, Y., . . . Horvath, T. L. (2010). Agrp neurons mediate Sirt1’s action on the melanocortin system and energy balance: Roles for Sirt1 in neuronal firing and synaptic plasticity. The Journal of Neuroscience, 30(35), 11815–11825.

Orlistat attenuates obesity‐induced decline in steroidogenesis and spermatogenesis by up‐regulating steroidogenic genes

Steroidogenesis decline is reported to be one of the mechanisms associated with obesity-induced male factor subfertility/infertility. We explored the possible preventive/therapeutic effects of orlistat (a medication prescribed for weight loss) on obesity-induced steroidogenesis and spermatogenesis decline. Twenty-four adult male Sprague Dawley rats weighing 250-300g were randomized into four groups (n=6/group), namely; normal control, high-fat diet, high-fat diet plus orlistat preventive group and high-fat diet plus orlistat treatment group. Orlistat (10mg/kg/b.w./d suspended in distilled water) was either concurrently administered with high-fat diet for 12weeks (high-fat diet plus orlistat preventive group) or administered from week 7-12 post- high-fat diet feeding (high-fat diet plus orlistat treatment group). Thereafter, serum, testes and epididymis were collected for analyses. Obesity increased serum leptin and decreased adiponectin levels, decreased serum and intra-testicular levels of follicle stimulating hormone, luteinising hormone and testosterone, sperm count, motility, viability, normal morphology and epididymal antioxidants, but increased epididymal malondialdehyde level and sperm nDNA fragmentation. Testicular mRNA transcript levels of androgen receptor, luteinizing hormone receptor, steroidogenic acute regulatory protein, cytochrome P450 enzyme (CYP11A1), 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase were significantly decreased in the testes of the high-fat diet group. Further, the levels of steroidogenic acute regulatory protein protein and enzymatic activities of CYP11A1, 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase were also significantly decreased in the testes of the high-fat diet group. Treatment with orlistat significantly decreased leptin and increased adiponectin levels, improved sperm parameters, decreased sperm DNA fragmentation, increased the levels of steroidogenic hormones, proteins and associated genes in high-fat diet-induced obese male rats, with the preventive group (high-fat diet plus orlistat preventive group) having better results relative to the treatment group (high-fat diet plus orlistat treatment group). Orlistat attenuated impaired spermatogenesis and steroidogenesis decline by up-regulating steroidogenic genes. This may not be unconnected to its significant effect in lowering serum leptin levels, since the hormone is known to dampen fertility potential. Therefore, orlistat may improve fertility potential in overweight/obese men.

A rodent model of partial intestinal diversion: a novel metabolic operation.

Metabolic surgery is safe and the most effective therapy for obesity and its co-morbidities. New procedures may allow for better tailoring of metabolic surgery to the individual patient. To evaluate the impact, comparative effectiveness, and mechanisms of the partial intestinal diversion (PID), vertical sleeve gastrectomy (VSG), and the combination of PID and VSG on weight and glucose regulation. University research facility, United States. Three cohorts of high-fat diet-induced obese male rats were randomized to distal PID (DPID), proximal PID (PPID), VSG, VSG and DPID (VSG/DPID), or sham operation (Sham). Animals were followed for 11 (cohort 1) or 10 (cohorts 2 and 3) weeks. Outcomes included weight and composition, food intake, glucose metabolism, lipids, bile acids, and energy balance. Statistical comparisons were performed using Tukey's multiple comparison test applied to analysis of variance. DPID and not PPID resulted in significant weight and body fat reductions relative to Sham. Improved glucose tolerance was seen in all surgical groups though this reached statistical significance for only DPID and VSG compared with Sham. Improvements in baseline glucose and insulin, corresponding insulin resistance, and plasma lipids were noted in DPID compared with Sham. Though the magnitude of weight and body composition changes and metabolic benefit tended to be larger for VSG relative to DPID, it only reached statistical significance for lipids. VSG and VSG/DPID resulted in similar outcomes. Markedly reduced food intake occurred after VSG and more modestly after DPID. Stool caloric content was higher in DPID relative to all groups. DPID is an effective metabolic operation resulting in notable weight and fat loss and metabolic improvement relative to sham-operated rodents. Interestingly, combining VSG with DPID added little additional benefit to the effects of VSG.

Cyclic glycine-proline normalizes systolic blood pressure in high-fat diet-induced obese male rats

Background and aimsInsulin-like growth factor (IGF)-1 deficiency is associated with a range of metabolic disorders. Cyclic glycine-proline (cGP) is a natural nutrient and regulates the amount of active IGF-1 in plasma. Plasma cGP decreases in hypertensive women whereas increases in obese women, suggesting its involvement in cardio-metabolic function. We therefore examined the effects of cGP on metabolic profiles and blood pressure in high-fat diet (HFD)-induced obese male rats. MethodsMale rats were fed either a HFD or a standard chow diet (STD) ad-libitum from 3 to 15 weeks of age. Rats were administered either saline or cGP from 11 to 15 weeks of age. At 14 weeks of age, systolic-blood pressure (SBP) was measured by tail-cuff plethysmography and body composition quantified by DEXA. Blood and retroperitoneal fat tissues were collected. Plasma concentrations of insulin, IGF-1, IGF binding protein (IGFBP)-3 and cGP were evaluated using ELISA and HPLC-MS respectively. ResultsCompared to STD, HFD feeding increased SBP, total fat mass and fat/lean ratio, retroperitoneal fat weight, fasting plasma insulin and cGP concentrations whereas decreased plasma IGF-1 and IGFBP-3 concentrations. Administration of cGP reduced SBP and retroperitoneal fat weight, but had no effect on body composition and plasma insulin concentrations. ConclusionHFD-associated decreases in IGFBP-3 and increases in cGP represent an autocrine response to normalize IGF-1 function through improving the amount of bioavailable IGF-1 in the circulation of obese male rats. The beneficial effects of cGP on SBP and retroperitoneal fat mass may suggest a therapeutic potential for cGP in HFD-associated cardio-metabolic complications.

Soy Isoflavones Ameliorate Fatty Acid Metabolism of Visceral Adipose Tissue by Increasing the AMPK Activity in Male Rats with Diet-Induced Obesity (DIO).

Soy isoflavones are natural active ingredients of soy plants that are beneficial to many metabolic diseases, especially obesity. Many studies have reported that obesity is closely related to visceral fatty acid metabolism, but the effect has not been well defined. In this study, we show that soy isoflavones improve visceral fatty acid metabolism in diet-induced obese male rats, which was indicated by reduced body weight and visceral fat cell area, as well as suppressed visceral fat synthesis and accelerated fat hydrolysis. We also found that common components of soy isoflavones, daidzein and genistein, were able to inhibit the lipid accumulation process in 3T3-L1 cells. Moreover, we showed that soy isoflavones can promote on AMP-activated protein kinase (AMPK) activity both in vivo and in vitro, which may be implicated in lipid metabolism regulation of soy isoflavones. Our study demonstrates the potential of soy isoflavones as a mechanism for regulating lipid homeostasis in visceral adipose tissue, proven to be beneficial for obesity treatment.

Potential Anti-obesogenic Effects of Ginkgo biloba Observed in Epididymal White Adipose Tissue of Obese Rats.

Exacerbated expansion of adipose tissue seen in diet-induced obesity leads to endocrine dysfunction and disturbance in adipokine secretion, with such abnormal profile positively associated with type 2 diabetes and other mild chronic inflammatory conditions. Ginkgo biloba extract (GbE), a mixture of polyphenols with antioxidant properties, has been recently investigated in a variety of experimental models of endocrine dysfunction, with several potentially beneficial effects identified, including improvement in insulin sensitivity in obese rats, and reduction of weight gain in ovariectomy-induced obesity and diet-induced obesity. The aim of this study was to investigate in high fat diet-induced obese male rats the effects of GbE supplementation for 2 weeks on adipocyte volume and adipose tissue lipid accumulation. GbE supplementation was effective in reducing energy intake in obese rats compared to the saline-treated placebo group. Epididymal adipocyte volume was reduced in GbE-supplemented rats, as were epididymal [1-14C]-acetate incorporation into fatty acids, perilipin (Plin 1) and fatty acid synthase (Fasn) mRNA, and FAS protein levels. Adipocyte hypertrophy in obesity is associated with insulin resistance, and in the present study we observed a reduction in the adipocyte volume of GbE-supplemented obese rats to dimensions equivalent to adipocytes from non-obese rats. GbE supplementation significantly reduced acetate accumulation and tended to reduce [3H]-oleate incorporation, into epididymal adipose tissue, suggesting a potentially anti-obesogenic effect in longer term therapies. Further studies that investigate the effects of GbE supplementation in other experimental models are required to fully elucidate its suggested beneficial effects on mild chronic inflammatory conditions.