Rodent Models Of Obesity Research Articles

A Missing Puzzle in Preclinical Studies-Are CCR2, CCR5, and Their Ligands' Roles Similar in Obesity-Induced Hypersensitivity and Diabetic Neuropathy?-Evidence from Rodent Models and Clinical Studies.

Research has shown that obesity is a low-grade inflammatory disease that is often associated with comorbidities, such as diabetes and chronic pain. Recent data have indicated that chemokines may play a role in these conditions due to their pronociceptive and chemotactic properties, which promote hypersensitivity and inflammation. Accumulating evidence suggests that CCR2, CCR5, and their ligands (CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11 CCL12, and/or CCL13) play a role in rodent models of pain and obesity, as well as in patients with diabetes and obesity. It was proven that the blockade of CCR2 and CCR5, including the simultaneous blockade of both receptors by dual antagonists, effectively reduces hypersensitivity to thermal and mechanical stimuli in chronic pain states, including diabetic neuropathy. The present review discusses these chemokine receptors and the role of their ligands in diabetes and obesity, as well as their involvement in diabetic neuropathy and obesity-induced hypersensitivity.

Hypoxia signaling in the adipose tissue.

Obesity per se is rapidly emerging all over the planet and further accounts for many other life-threatening conditions, such as diabetes, cardiovascular diseases, and cancers. Decreased oxygen supply or increased relative oxygen consumption in the adipose tissue results in adipose tissue hypoxia, which is a hallmark of obesity. This review aims to provide an up-to-date overview of the hypoxia signaling in the adipose tissue. First, we summarize literature evidence to demonstrate that hypoxia is regularly observed during adipose tissue remodeling in human and rodent models of obesity. Next, we discuss how hypoxia-inducible factors (HIFs) are regulated and how adipose tissues behave in response to hypoxia. Then, the differential roles of adipose HIF-1α and HIF-2α in adipose tissue biology and obesity pathology are highlighted. Finally, the review emphasizes the importance of modulating adipose hypoxia as a therapeutic avenue to assist adipose tissues in functionally adapting to hypoxic conditions, ultimately promoting adipose health and improving outcomes due to obesity.

Anti-obesity effects of potential probiotic Lactobacillus strains isolated from Mongolian fermented dairy products in high-fat diet-induced obese rodent model.

This study aims to investigate the anti-obesity properties of lactic acid bacteria (LAB) isolated from fermented dairy products such as "Airag" and "Khoormog" in Mongolia. These traditional dairy products are widely used in Mongolia and believe in having potential probiotic, anti-diabetes, anti-cancer, and anti-tuberculosis properties and are made from unheated two-humped camel milk and mare milk, respectively. We chose three LAB strains based on their probiotic characteristics, including tolerance of gastric and bile acids. Then we checked the anti-obesity activity of probiotic strains in vivo. An animal model was evaluated in twenty male C57BL/6J mice by inducing obesity with a high-fat diet (HFD), which was divided into five groups: regular diet group (Negative control), HFD group (Positive control), HFD with Lacticaseibacillus paracasei X-1 (X-1), Lacticaseibacillus paracasei X-17 (X-17), and Limosilactobacillus fermentum BM-325 (BM-325). For six weeks, 5 × 109 colony-forming units (CFU) of bacteria were given orally to the LAB-fed groups. Fasting blood glucose (FBG), lipid profiles, organ index, and organ morphology were all measured. The probiotic strains suppressed growth in adipose cell volume, stabilized FBG, reduced liver cell degeneration, and slowed HFD-induced body weight gain. The results suggest that some strains increase general metabolism while lowering body weight.

Abstract PS07-08: Bazedoxifene plus conjugated estrogen reduces mammary proliferation markers and improves adipocyte size, gut microbiome, and metabolic health: Findings from a preclinical model of obesity and breast cancer risk

Abstract Background: Many women at high risk for breast cancer will not take tamoxifen or aromatase inhibitors for cancer prevention due to concern of side effects including hot flashes. Further, tamoxifen has detrimental metabolic effects in some overweight/obese women. Duavee®, a tissue-selective complex of bazedoxifene + conjugated estrogen, is FDA-approved for relief of hot-flashes and prevention of osteoporosis. Preclinical studies suggest favorable metabolic effects and potential for breast cancer risk reduction. In a single arm clinical trial, BZA+CE reduced Ki-67 and mammographic density (PMID: 31420361), and this combination is currently being assessed further in a Phase IIB trial of postmenopausal high risk women with vasomotor symptoms. Here, we examined the modifying effects of obesity on response to BZA+CE in a rodent model of obesity and breast cancer risk. Methods: Rats received carcinogen at 7-weeks of age to induce mammary tumors and were fed a high-fat diet (46% kcal fat) to promote obesity. Lean and obese rat were selected based on adiposity at 16 weeks. Separate cohorts of lean and obese ovary-intact or ovariectomized (OVX) rats were randomized to a daily dose of BZA+CE or placebo control for 8 weeks. We assessed tumor development throughout the study and end of study RNA from mammary glands was analysed by gene expression microarray (Affymetrix). We also analyzed body weight/composition, markers of metabolic health (circulating glucose, insulin, adiponectin), as well as changes in the gut microbiome (metagenomic sequencing on DNA isolated from baseline and end-of-study fecal samples) in response to BZA+CE. Results: BZA+CE improved metabolic health in both ovary intact and OVX rats, including reduced body weight and % body fat, particularly in the visceral regions. These effects were greater in obese rats compared to lean. BZA+CE reduced the number of large adipocytes and increased small (insulin sensitive) adipocytes in the mammary adipose, indicating benefical changes in local tumor microenvironment. We found no evidence that Duavee® promoted tumor development or growth in ovary-intact or OVX’d rats. Gene set enrichment analysis (GSEA) of microarray data showed enrichment of cell proliferation pathways in MG from obese rats and these same pathways were downregulated with BZA+CE, consistent with anti-cancer effects. Analysis of the microbiome found that BZA+CE increased proportional abudance of Odoribacter laneus in the gut, regardless of lean/obese or intact/OVX status. Previous studies have demonstrated that this bacterim improves glucose control and reduces inflammatory cytokines when administered to obese mice, suggesting a possible mechanistic link in this study. Conclusions: Unlike traditional SERMs that can have negative metabolic effects, BZA+CE improved whole body and mammary gland metabolic health and reduced expression of cell proliferation pathways, particularly in obese rats. Prelminary data suggest that changes in the gut microbiome could contribute, at least in part, to these effects. Together this supports BZA+CE (Duavee) as an agent with potential beneficial effects on breast cancer risk reduction and improvements in metabolic health in women with obesity. Further analyses will guide assessment of outcomes in an ongoing parallel clinical study in postmenopausal women at high risk for breast cancer. Citation Format: Katherine L. Cook, Ramsey Jenshcke, Karen Corleto, Carol Fabian, Stephen Hursting, Bruce Kimler, Danilo Landrock, Erin Giles. Bazedoxifene plus conjugated estrogen reduces mammary proliferation markers and improves adipocyte size, gut microbiome, and metabolic health: Findings from a preclinical model of obesity and breast cancer risk [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS07-08.

Endothelin A Receptor Activation on Vascular Smooth Muscle Cells Mediates Visceral Adipose Tissue Inflammation in an Obese Mouse Model

Obesity causes a pro-inflammatory shift in visceral adipose tissue immune cells that is thought to promote adipocyte dysfunction and obesity pathophysiology. Endothelin-1 (ET-1) is a small peptide produced mostly by endothelial cells that causes inflammation in diseases including a number of nephropathies and autoimmune diseases. ET-1 is increased in obese patients and in rodent models of obesity. Our lab has demonstrated that mice fed high fat diet (HFD) have an increase in visceral adipose tissue CD4+ and CD8+ T cells and a reduction in anti-inflammatory eosinophils that is attenuated by treatment with an ET-1 type A receptor (ETAR) antagonist; however, the mechanisms by which ET-1 leads to inflammation remain unknown. The ETAR is highly abundant on vascular smooth muscle cells (VSMC), where activation causes a significant increase in pro-inflammatory interleukin-6 production. We hypothesized that elevated ET-1 production in visceral adipose causes a pro-inflammatory shift in tissue immune cells by activating VSMC ETAR. To test this hypothesis, 8-week-old floxed control and vascular smooth muscle cell-specific ETA knockout (SMAKO) mice were placed on either normal (n=5 and 3 for control and SMAKO respectively) or high-fat diet (n=6 and 4 for control and SMAKO respectively) for 12 weeks. Tissue immune cells were quantified by flow cytometry. As expected, HFD fed mice had significantly increased body weight, lean mass, and fat mass, as measured by EchoMRI, compared to NMD fed mice; however, there was no detectable difference due to genotype. There was a significant increase in CD4+ T cells (control NMD: 2.45 ± 0.28 vs. control HFD: 4.37 ± 0.80 % of CD45+ cells; SMAKO NMD: 0.94 ± 0.52 vs. SMAKO HFD: 2.24 ± 0.40 % of CD45+ cells; pint=0.63, pdiet=0.02*, pgenotype=0.01*) and CD8+ T cells (control NMD: 0.49 ± 0.10 vs. control HFD: 2.02 ± 0.59 % of CD45+ cells; SMAKO NMD: 0.12 ± 0.07 vs. SMAKO HFD: 0.52 ± 0.07 % of CD45+ cells; pint=0.20, pdiet=0.04*, pgenotype=0.04*) that was significantly attenuated in SMAKO mice. In addition, HFD fed control mice had a greater reduction in eosinophils compared to NMD floxed control. The reduction in eosinophils was attenuated in SMAKO (control NMD: 5.28 ± 2.01 vs. control HFD: 1.28 ± 0.07 % of CD45+ cells; SMAKO NMD: 5.92 ± 0.94 vs. SMAKO HFD: 4.49 ± 1.60 % of CD45+ cells; pint=0.42, pdiet=0.09, pgenotype=0.23). These data suggest that ET-1-induced adipose tissue inflammation in obese mice occurs via activation of ETAR on VSMCs. R01DK124437, P30GM149404, and T32HL105324. This is the full abstract presented at the American Physiology Summit 2024 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.

Hyperoxia impacts heme oxygenase 1 and mitochondrial quality control in a rodent model of sarcopenic obesity

Critically ill sarcopenic obese (SO) patients may be at higher risk for other complications and require mechanical ventilation, extending length of stay and recovery time. It may be because in sarcopenia and obesity, oxidants, inflammation and mitochondrial fragmentation increase, impacting respiration. Heme oxygenase 1 (HO-1) is an enzyme critical for cellular antioxidant and anti-inflammatory defenses, and in the regulation of mitochondrial quality control (MQC). Whether HO-1 signaling is impaired in SO during heightened oxidant stress remains unknown, the hypothesis of this research. Young (7-week-old) and old (72-week-old) C57BL/6J mice consumed high-fat (58%) or control (11% fat) diets for 16-weeks. Mean body weight (g), glucose AUC and strength (N) (±SD) measured after dietary interventions were as follows: young lean (33±2, 540±220, 1.9±0.3), young obese (53±3, 710±116, 1.8±0.4), old lean (38±4, 597±148, 1.5±0.3), and old obese (57±10, 654±119, 1.4±0.2). To induce oxidant stress, mice were exposed to 100% oxygen for 48 h. Lower hindlimb skeletal muscle was harvested 16 h later. Oxidant stress and inflammation were determined by measuring superoxide (DHE), DNA oxidation (8-OHdG), mitochondrial DNA lesions and cytochrome b mRNA, and IL-10, IL-1β and TNF-α protein expression. MQC was assessed by measuring regulators of mitochondrial fission (DRP1) and fusion (MFN1 and 2), mitophagy (PINK1, Parkin and LC3-II), and mitochondrial biogenesis (NFE2L2, PGC-1α, NRF1 and 2, and TFAM). The mitochondrial membrane potential was measured using TMRM. In contrast to air controls where HO-1 protein expression was increased by aging and obesity, hyperoxia caused substantial reductions in both HO-1 protein and mRNA within old and obese mice. The greatest reductions were found in SO (25% of young lean). The changes in HO-1 were accompanied by the following responses to hyperoxia: One, superoxide and DNA oxidation increased in old and obese mice by as much as 200%, leading to elevated mitochondrial DNA lesions and reduced cytochrome b. Two, IL-1β and TNF-α increased in aged mice by 41-129% over young mice, whereas IL-10 was lower (-33%) only in SO. Three, regulators of mitochondrial fission and fusion and mitophagy were reduced by aging and obesity, being lower in sarcopenia which may explain why mitochondrial LC3-II was only reduced in these mice. Fourth, modulators of mitochondrial biogenesis were decreased by aging and obesity, suggesting a reduced mitochondrial population. Lastly, the increased mitochondrial membrane potential measured in young obese (78%) and old lean (58%) mice was not observed in SO, indicating reduced mitochondrial activity. In sarcopenic and obese mice exposed to hyperoxia, oxidant stress and mitochondrial DNA fragmentation increase without a concomitant change in MQC to maintain a healthy and functional mitochondrial network. Suppression of HO-1 may be a mechanism for these changes during periods of hyperoxic stress in sarcopenia and obesity that contribute to poor outcomes in critical illness. This work was supported by the Developing Research Excellence in Anesthesia Management Innovation Grant (2021). This is the full abstract presented at the American Physiology Summit 2024 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.

Development of a Novel Assay for Direct Assessment of Selective Amylin Receptor Activation Reveals Novel Differences in Behavior of Selective and Nonselective Peptide Agonists.

Dual amylin and calcitonin receptor agonists (DACRAs) show promise as efficacious therapeutics for treatment of metabolic disease, including obesity. However, differences in efficacy in vivo have been observed for individual DACRAs, indicating that detailed understanding of the pharmacology of these agents across target receptors is required for rational drug development. To date, such understanding has been hampered by lack of direct, subtype-selective, functional assays for the amylin receptors (AMYRs). Here, we describe the generation of receptor-specific assays for recruitment of Venus-tagged Gs protein through fusion of luciferase to either the human calcitonin receptor (CTR), human receptor activity-modifying protein (RAMP)-1, RAMP1 (AMY1R), human RAMP2 (AMY2R), or human RAMP3 (AMY3R). These assays revealed a complex pattern of receptor activation by calcitonin, amylin, or DACRA peptides that was distinct at each receptor subtype. Of particular note, although both of the CT-based DACRAs, sCT and AM1784, displayed relatively similar behaviors at CTR and AMY1R, they generated distinct responses at AMY2R and AMY3R. These data aid the rationalization of in vivo differences in response to DACRA peptides in rodent models of obesity. Direct assessment of the pharmacology of novel DACRAs at AMYR subtypes is likely to be important for development of optimized therapeutics for treatment of metabolic diseases. SIGNIFICANCE STATEMENT: Amylin receptors (AMYRs) are important obesity targets. Here we describe a novel assay that allows selective functional assessment of individual amylin receptor subtypes that provides unique insight into the pharmacology of potential therapeutic ligands. Direct assessment of the pharmacology of novel agonists at AMYR subtypes is likely to be important for development of optimized therapeutics for treatment of metabolic diseases.

Metabolomic Alteration in Adipose Monocyte Chemotactic Protein-1 Deficient Mice Fed a High-Fat Diet.

Monocyte chemotactic protein-1 (MCP-1), a small inducible cytokine, is involved in obesity-related chronic disorders. Adipocytes produce MCP-1 that is elevated in obese humans and in rodent models of obesity. This study examined the hepatic metabolomic alterations caused by adipose-specific MCP-1 deficiency in a rodent model of obesity. Wide-type (WT) and adipose-specific Mcp-1 knockdown mice (Mcp-1 -/-) were each assigned randomly to 2 groups and fed the standard AIN93G diet or a high-fat diet (HFD) for 12 weeks. Compared to the AIN93G diet, the HFD increased body weight, body fat mass, and plasma concentrations of insulin and leptin, regardless of genotype. There were no differences in these variables between WT and Mcp-1 -/- mice when they were fed the same diet. Eighty-seven of 172 identified metabolites met the criteria for metabolomic comparisons among the 4 groups. Thirty-nine metabolites differed significantly between the 2 dietary treatments and 15 differed when Mcp-1 -/- mice were compared to WT mice. The metabolites that significantly differed in both comparisons included those involved in amino acid, energy, lipid, nucleotide, and vitamin metabolism. Network analysis found that both HFD and adipose Mcp-1 knockdown may considerably impact amino acid metabolism as evidenced by alteration in the aminoacyl-tRNA biosynthesis pathways, in addition to alteration in the phenylalanine, tyrosine, and tryptophan biosynthesis pathway in Mcp-1 -/- mice. However, decreased signals of amino acid metabolites in mice fed the HFD and increased signals of amino acid metabolites in Mcp-1 -/- mice indicate that HFD may have down-regulated and adipose Mcp-1 knockdown may have up-regulated amino acid metabolism.

Prolactin-Releasing Peptide, a Peptide with an Improper Name, but Proper Biological Activity for Obesity, Type-2 Diabetes, and Alzheimer's Disease Treatment

Obesity is an escalating epidemic, but an effective non-invasive therapy is still scarce. For the obesity treatment, anorexigenic neuropeptides represent promising tools, but their delivery from the periphery to the brain is complicated because peptides have a low stability and limited ability to cross the blood-brain barrier. Recently discovered anorexigenic neuropeptides, such as prolactin-releasing peptide, represent new trends in development of anti-obesity agents. They are released and acting directly in brain areas regulating food intake, but generally do not cross the blood-brain barrier if administered peripherally. We succeeded to design stable palmitoylated analogs of this neuropeptide with a prolonged acute anorexigenic effect after peripheral administration as shown in mice and rats. Repeated peripheral administration of the lipidized prolactin-releasing peptide analogs resulted in long-lasting anti-obesity and antidiabetic effects in rodent models of diet-induced obesity and insulin resistance. We proved that lipidation might be an effective way to transmit the desired effect to the central nervous system after peripheral administration, for a potential treatment of obesity and related complications such as type-2 diabetes. Besides the advanced age, type-2 diabetes and obesity were shown to be risk factors for Alzheimer's disease; therefore, compounds with glucose-lowering and/or anorexigenic properties were proposed to be neuroprotective. In our group, we studied a possible crosstalk between obesity, type-2 diabetes and Alzheimer's-like pathology. We also investigated if our novel palmitoylated analogs of prolactin-releasing peptide could have beneficial effect on neurodegeneration in several mouse models of Alzheimer's-like pathology and their age-matched wild type controls. We demonstrated that these lipidized analogs are potentially neuroprotective substances improving spatial memory, neurogenesis, synaptogenesis and attenuating neuroinflammation and two hallmarks of Alzheimer's disease, i.e., tau hyper-phosphorylation and β-amyloid plaques in different mouse models of Alzheimer's-like neurodegeneration.

Comparison of three different anastomotic methods of sleeve gastrectomy with transit bipartition using an obese rodent model

The long-term effects and safety of single-anastomosis sleeve ileal (SASI) bypass have not been confirmed. The one anastomosis procedure carries the risk of bile reflux, and Braun anastomosis has the capacity to reduce bile reflux. This study was designed to compare the influences of bile reflux and histological changes in the esogastric sections of rats. Obese Sprague–Dawley rats underwent sleeve gastrectomy with transit bipartition (RYTB) (n = 12), SASI (n = 12), SASI bypass with Braun anastomosis (BTB) (n = 12), esojejunostomy (EJ) (n = 12), and SHAM (n = 8) surgery. During the 12-week follow-up period, weight changes, glucose improvement, and changes in serum nutrition were evaluated. Histological expression and bile acid concentration in the rats in all groups were also evaluated. No significant differences in weight loss and glucose improvements were observed in the RYTB, SASI, and BTB groups. The RYTB and BTB groups had significantly lower bile acid concentration and albumin levels than the SASI group. In addition, mucosal height in the RYTB and BTB groups was significantly lower than in the SASI group. Braun anastomosis had a significant effect on anti-reflux. BTB may be a superior primary procedure due to its potential for parallel bariatric and metabolic improvements, effective anti-reflux effects, simplified operations, and avoidance of severe malnutrition. Further clinical studies are needed to confirm these findings.

Short‐term high‐fat diet feeding induces cognitive decline, aggressiveness and anxiety‐like behavior in adult zebrafish (Danio rerio)

AbstractBackgroundObesity is a high‐ prevalence (13% of adult population in 2016), global health concern defined by a high body mass index (BMI). Several comorbidities are associated, including some affecting central nervous system (CNS), i.e. neurodegenerative diseases, cognitive deficit and psychobehavioral disturbs.MethodZebrafish has raised as a versatile and cheap model widely used to study human diseases, including obesity and neurological diseases. Therefore, our objective is verify the impact of a high‐fat diet on the central nervous system (CNS) using well‐ stablished behavioral tests. Animals was feed according with three dietary groups. The standard diet group (SD) received only 7.5 mg/fish of dry food, while the high‐fat diet groups received 5 mg/fish dry food plus 7.5 (HFD‐7.5) or 15 mg/fish (HFD‐15) of chicken egg yolk. Dietary fat content (w/w) was approximately 6.5%, 16.9% and 21.1%, respectively. After two weeks of diets ingestion, behaviors were assessed.ResultBoth HFD groups had obesogenic effects, indicated by increase on BMI, abdominal length and body weight compared with SD group. We show a HFD ingestion induced aggressive and anxiety‐like behavior on zebrafish, as measured by mirror‐induced aggression and novel tank diving test, respectively. Also, the higher concentration of HFD (HFD‐15) elicited cognitive deficit on inhibitory avoidance test while sociability was unaffected, as determined by the social preference test.ConclusionOur results are in accordance with evidences in obese human and rodent models, suggesting similar effects of fat intake. Therefore, we highlight the unexplored potential of zebrafish to elucidate this study field.

Effect of combined administration of Acyl-CoA: Cholesterol acyltransferase 1 inhibitor and glucagon-like peptide 1 receptor agonist on a rodent model of diet-induced obesity

A glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide was approved for the treatment of obesity by the Food and Drug Administration. However, it can cause gastrointestinal events at high doses, limiting its broader use. Combining drugs with multiple mechanisms of action could enhance the weight-reducing effects while minimizing side effects. To this end, we investigated the combined effects of semaglutide and avasimibe, an acyl-CoA:cholesterol acyltransferase 1 (ACAT1) inhibitor, on weight reduction in diet-induced obesity mice. Two cohorts of mice were used: In cohort 1, mice were fed a high-fat (HF) diet for 12 weeks and then randomly assigned to the vehicle, avasimibe [10 mg/kg body weight (BW)], semaglutide (0.4 mg/kg BW), or combination groups. The drugs were administered via subcutaneous (sc) injections on a daily basis. In cohort 2, mice were fed an HF diet for 8 weeks and randomly assigned to the same four groups, but avasimibe was administered at a dose of 20 mg/kg BW, and the drugs were administered every 3 days. In cohort 1, semaglutide initially reduced food intake initially, but this effect was diminished with prolonged administration. Avasimibe, on the other hand, did not affect food intake but prevented weight gain to a lesser extent than semaglutide. Importantly, the combination treatment resulted in the greatest percentage of body weight reduction, along with lower plasma glucose and leptin levels compared to the semaglutide single-treatment group. Cohort 2 confirmed that the superior weight loss in the combination group compared to the other three groups was largely due to a significant reduction in fat mass. Histological analysis of inguinal adipose tissue showed smaller adipocyte size across all treatment groups compared to the vehicle group, with no significant differences among the treatment groups. Collectively, these findings suggest combining semaglutide and avasimibe could be an effective approach to weight management.

Metaphorical investigation of aqueous distillate of Cichorium intybus, Foeniculum vulgare and Solanum nigrum along with atorvastatin and orlistat in experimental rodent models of dyslipidaemia and obesity

BackgroundArq is a traditional Unani liquid formulation. In this study we explored Arq-Makoh, Arq-Badiyan and Arq-Kasni for their pharmacological potential to alleviate the symptoms of hyperlipidaemia and obesity and develop an amalgamation with modern drugs that have clinically well reported antihyperlipidaemic and antiobesity potential. Materials and methodsRats were fed High Fat Diet for 4 weeks. 10 ​ml/kg of each of the three arqs were given alone and along with atorvastatin and orlistat daily for 28 days P.O. During the course of treatment body weight and food intake were carefully observed and after the end of the study, liver weight, heart weight, plasma lipid profile, blood glucose level, insulin and leptin level, serum lipase, lactate dehydrogenase, and antioxidant activity were studied in all treatment groups. ResultBoth Arqs and Atorvastatin and Orlistat significantly reduced body weight, lipid profile in HFD fed rats. Arqs when given along with Atorvastatin and Orlistat produced more significant decrease in the serum lipid profile, serum lipase, atherogenic index, lactate Dehydrogenase and TBARS compared with HFD Control group and elevated the levels of HDL-C and SOD. Apart from antihyperlipidaemic and antiobesity effects the treatment groups showed a significant reduction in elevated fasting blood glucose levels (as a result of HFD model used in the study). The above parameters were further confirmed by histopathological studies. ConclusionThe present study indicates that Arq-Makoh, Arq-Badiyan and Arq-Kasni has lipid lowering potential and could potentiate the antihyperlipidaemic and antiobesity potential of Atorvastatin and Orlistat.

Reducing Effect of a Standardized Extract of Apple Branches on Food Intake in Healthy, Nonobese Rats

Literature data suggest that apple-derived products, including phenol-enriched extracts, may reduce food intake in rodent models of diet-induced obesity. With the intent of further expanding this research issue, the present study investigated the effect of an apple branch extract (ABE)—standardized for the polyphenol, phlorizin (22.93%)—on regular food intake in healthy, nonobese Wistar rats. Rats were given unlimited access to standard food pellets and water in the homecage. Acute, intragastric treatment with ABE (0, 300, and 900 mg/kg) effectively and selectively reduced food intake. The effect of 900 mg/kg ABE was closely replicated by acute treatment with 200 mg/kg pure phlorizin, suggesting that this was the likely active ingredient underlying the effect of ABE on food intake. These results further strengthen the hypothesis that apple-derived products may represent a promising option for novel pharmacotherapies for eating disorders and overweight.

Trans-palmitoleic acid does not modify the inflammasome expression in a rodent model of diet-induced obesity.

Metabolic disorders such as obesity and type 2 diabetes (T2D) coincide with an increased expression of pro-inflammatory factors. The NLRP3 inflammasome is a complex that activates the pro-inflammatory cytokine IL-1β. (NOD-like receptor protein 3). Some nutrients, such as fatty acids, influence inflammatory processes. For example, in clinical studies, higher trans-palmitoyl acid (TP) concentrations coincide with lower adiposity and lower risk of developing T2D. This study aims to evaluate the effect of TP on NLRP3 expression in a rodent model of diet-induced obesity (DIO). C57BL/6J mice were fed ad libitum with a control or a high-fat diet (HFD), added with or without TP (3 g/kg diet), for 11 weeks. IL-1β was quantified in serum, and NLRP3-related gene expression was explored in epididymal adipose tissue. Despite increased weight gain in both high-fat groups, the high-fat TP group gained less weight than the high-fat group. In addition, NLRP3 and caspase-1 expression was higher in the HFD groups, but no differences were observed between the HFD and the HFD TP groups. Serum IL-1β levels were not different among groups. Diet supplementation with TP prevents weight gain and has a neutral influence over NLRP3 expression and IL-1β concentration in a DIO mice model.

Childhood obesity is linked to putative neuroinflammation in brain white matter, hypothalamus, and striatum.

Neuroinflammation is both a consequence and driver of overfeeding and weight gain in rodent obesity models. Advances in magnetic resonance imaging (MRI) enable investigations of brain microstructure that suggests neuroinflammation in human obesity. To assess the convergent validity across MRI techniques and extend previous findings, we used diffusion basis spectrum imaging (DBSI) to characterize obesity-associated alterations in brain microstructure in 601 children (age 9-11years) from the Adolescent Brain Cognitive DevelopmentSM Study. Compared with children with normal-weight, greater DBSI restricted fraction (RF), reflecting neuroinflammation-related cellularity, was seen in widespread white matter in children with overweight and obesity. Greater DBSI-RF in hypothalamus, caudate nucleus, putamen, and, in particular, nucleus accumbens, correlated with higher baseline body mass index and related anthropometrics. Comparable findings were seen in the striatum with a previously reported restriction spectrum imaging (RSI) model. Gain in waist circumference over 1 and 2 years related, at nominal significance, to greater baseline RSI-assessed restricted diffusion in nucleus accumbens and caudate nucleus, and DBSI-RF in hypothalamus, respectively. Here we demonstrate that childhood obesity is associated with microstructural alterations in white matter, hypothalamus, and striatum. Our results also support the reproducibility, across MRI methods, of findings of obesity-related putative neuroinflammation in children.

Corchorus olitorius extract exhibit anti-hyperglycemic and anti-inflammatory properties in rodent models of obesity and diabetes mellitus.

Obesity and type 2 diabetes (T2D) are chronic conditions with detrimental impacts on the overall health of individuals. Presently, the use of pharmacological agents in obesity and T2D offers limited benefits and pose side effects. This warrant studies on remedies that are less toxic and inexpensive while effective in ameliorating secondary complications in obesity and T2D. Plant-based remedies have been explored increasingly due to their remarkable properties and safety profile. We searched for pre-clinical evidence published from inception until 2023 on PubMed, Scopus, Google, and Semantic scholar on Corchorus olitorius (C. olitorius) in both obesity and T2D. Our focus was to understand the beneficial impact of this plant-based remedy on basic glycemic, lipid, inflammatory, and biomarkers of oxidative stress. The evidence gathered in this review suggests that C. olitorius treatment may significantly reduce blood glucose, body weight, total cholesterol, triglycerides, and low-density lipoprotein (LDL) in concomitant with increasing high-density lipoprotein-cholesterol (HDL-c) in rodent models of obesity and T2D. Interestingly, this effect was consistent with the reduction of malonaldehyde, superoxide dismutase and catalases, tumor necrosis factor-alpha, interleukins, and leptin. Some of the mechanisms by which C. olitorius reduces blood glucose levels is through stimulation of insulin secretion, increasing β-cell proliferation, thus promoting insulin sensitivity; the process which is mediated by ascorbic acid present in this plant. C. olitorius anti-hyperlipidemia is attributable to the content of ferulic acid found in this plant, which inhibits 3-Hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors and thus results in reduced synthesis of cholesterol and increased hepatic LDL-c receptor expression, respectively. The present review provides extensive knowledge and further highlights the potential benefits of C. olitorius on basic metabolic parameters, lipid profile, inflammation, and oxidative stress in rodent models of obesity and T2D.

TAAR1 Agonist Ulotaront Improves Glycemic Control and Reduces Body Weight in Rodent Models of Diabetes, Obesity, and Iatrogenic Weight Gain

AbstractIntroductionPreclinical evidence has identified the trace amine-associated receptor 1 (TAAR1) as a novel regulator of metabolic control. Ulotaront is a TAAR1 and 5-HT1A agonist currently in Phase 3 clinical trials for the treatment of schizophrenia. Here we summarize preclinical results assessing the effects of ulotaront on weight and metabolic parameters.MethodsEffects of ulotaront administration were evaluated on oral glucose tolerance (oGTT), gastric emptying, and in rodent models of weight gain (high-fat diet [HFD]-, corticosterone-, and olanzapine-induced).ResultsFollowing 15-day oral administration of ulotaront, rats on HFD showed dose-dependent reduction in body weight, food intake, and liver triglyceride content compared to controls. In addition, a more rapid reversal of olanzapine-induced weight gain and food intake was observed in rats switched to ulotaront (vs. vehicle). Consistent with weight-lowering effects in rats, chronic ulotaront treatment normalized corticosterone-induced weight gain in mice. Assessment of oGTT showed a dose-dependent reduction of glucose excursion in response to acute ulotaront administration in naive and diabetic db/db mice. Ulotaront administration also delayed gastric emptying in mice—a likely mechanism driving reductions in glucose excursions during the oGTT. Whole-brain c-fos imaging of ulotaront-treated mice revealed increased neuronal activity in several brain regions associated with regulation of food intake and metabolic signals.ConclusionsThe data indicate that ulotaront not only lacks metabolic liabilities typically associated with antipsychotics but can reduce body weight and improve glucose tolerance in rodent models. The underlying mechanisms may include TAAR1-mediated peripheral effects on glucose homeostasis and/or direct modulation of homeostatic and hedonic neurocircuits regulating energy balance. The beneficial metabolic effects of ulotaront may suggest a substantially improved risk-benefit profile compared to established antipsychotics.FundingSunovion Pharmaceuticals Inc. and Otsuka Pharmaceutical Development & Commercialization, Inc.

Crosstalk between Adipose Tissue and Hepatic Mitochondria in the Development of the Inflammation and Liver Injury during Ageing in High-Fat Diet Fed Rats.

Obesity is considered an epidemic disorder, due to an imbalance between energy consumption and metabolizable energy intake. This balance is increasingly disrupted during normal aging processes due to the progressive impairment of mechanisms that normally control energy homeostasis. Obesity is triggered by an excessive lipid depots but reflects systemic inflammation along with large adipocytes secreting proinflammatory adipokines, an increase of the free fatty acids levels in the bloodstream, and ectopic lipid accumulation. Hepatic fat accumulation is the most common cause of chronic liver disease, characterized by mitochondrial dysfunction with a consequent impaired fat metabolism and increased oxidative stress. Therefore, mitochondrial dysfunction is associated to hepatic lipid accumulation and related complications. In this study, we assessed the crosstalk between adipose tissue and liver, analyzing the time-course of changes in hepatic mitochondrial fatty acid oxidation capacity versus fatty acid storage, focusing on the contribution of adipose tissue inflammation to hepatic lipid accumulation, using a rodent model of high fat diet-induced obesity. Our results demonstrate that both high-fat diet-induced obesity and aging induce dysregulation of adipose tissue function and similar metabolic alterations mediated by mitochondrial function impairment and altered inflammatory profile. The high fat diet-induced obesity anticipates and exacerbates liver mitochondrial dysfunction that occurs with aging processes.

Exogenous succinate impacts mouse brown adipose tissue mitochondrial proteome and potentiates body mass reduction induced by liraglutide.

Obesity is one of the leading noncommunicable diseases in the world. Despite intense efforts to develop strategies to prevent and treat obesity, its prevalence continues to rise worldwide. A recent study has shown that the tricarboxylic acid intermediate succinate increases body energy expenditure by promoting brown adipose tissue thermogenesis through the activation of uncoupling protein-1; this has generated interest surrounding its potential usefulness as an approach to treat obesity. It is currently unknown how succinate impacts brown adipose tissue protein expression, and how exogenous succinate impacts body mass reduction promoted by a drug approved to treat human obesity, the glucagon-like-1 receptor agonist, liraglutide. In the first part of this study, we used bottom-up shotgun proteomics to determine the acute impact of exogenous succinate on the brown adipose tissue. We show that succinate rapidly affects the expression of 177 brown adipose tissue proteins, which are mostly associated with mitochondrial structure and function. In the second part of this study, we performed a short-term preclinical pharmacological intervention, treating diet-induced obese mice with a combination of exogenous succinate and liraglutide. We show that the combination was more efficient than liraglutide alone in promoting body mass reduction, food energy efficiency reduction, food intake reduction, and an increase in body temperature. Using serum metabolomics analysis, we showed that succinate, but not liraglutide, promoted a significant increase in the blood levels of several medium and long-chain fatty acids. In conclusion, exogenous succinate promotes rapid changes in brown adipose tissue mitochondrial proteins, and when used in association with liraglutide, increases body mass reduction.NEW & NOTEWORTHY Exogenous succinate induces major changes in brown adipose tissue protein expression affecting particularly mitochondrial respiration and structural proteins. When given exogenously in drinking water, succinate mitigates body mass gain in a rodent model of diet-induced obesity; in addition, when given in association with the glucagon-like peptide-1 receptor agonist, liraglutide, succinate increases body mass reduction promoted by liraglutide alone.