Attenuated Body Weight Gain Research Articles

Moderate-intensity aerobic exercise enhanced dopamine signaling in diet-induced obese female mice without preventing body weight gain

Obesity continues to rise in prevalence and financial burden despite strong evidence linking it to an increased risk of developing several chronic diseases. Dopamine response and receptor density are shown to decrease under conditions of obesity. However, it is unclear if this could be a potential mechanism for treatment without drugs that have a potential for abuse. Therefore, the aim of this study was to investigate whether moderate-intensity exercise could reduce body weight gain and the associated decreases in dopamine signaling observed with high-fat diet-induced adiposity. We hypothesized that exercise would attenuate body weight gain and diet-induced inflammation in high-fat (HF)-fed mice, resulting in dopamine signaling (release and reuptake rate) comparable to sedentary, low-fat (LF)-fed counterparts. This hypothesis was tested using a mouse model of diet-induced obesity (DIO) and fast-scan cyclic voltammetry to measure evoked dopamine release and reuptake rates. Although the exercise protocol employed in this study was not sufficient to prevent significant body weight gain, there was an enhancement of dopamine signaling observed in female mice fed a HF diet that underwent treadmill running. Additionally, aerobic treadmill exercise enhanced the sensitivity to amphetamine (AMPH) in this same group of exercised, HF-fed females. The estrous cycle might influence the ability of exercise to enhance dopamine signaling in females, an effect not observed in male groups. Further research into females by estrous cycle phase, in addition to determining the optimal intensity and duration of aerobic exercise, are logical next steps.

Lactobacillus paracasei subsp. paracasei NTU 101 prevents obesity by regulating AMPK pathways and gut microbiota in obese rat

This study assessed the anti-obesity effects of Lactobacillus paracasei subsp. paracasei NTU 101 (NTU 101) both in vitro and in vivo. Initially, the cytotoxicity and lipid accumulation inhibitory effects of NTU 101 on 3T3-L1 cells were evaluated using the MTT assay and oil red O assay, respectively. Subsequently, the anti-obesity effects of NTU 101 were investigated in high-fat diet-induced obese rat. Moreover, western blotting was performed to measure the obesity-related protein expression of PPARα, PPARβ, PPARγ, C/EBPα, C/EBPβ, ATGL, p-p38 MAPK, p-ERK1/2, p-AMPK and CPT-1 in both 3T3-L1 adipocytes and adipose and liver tissues. Treatment with 16 × 108 CFU/mL NTU 101 reduced lipid accumulation in 3T3-L1 adipocytes by more than 50 %. Oral administration of NTU 101 significantly attenuated body weight gain, as well as adipose tissue weight. NTU 101 administration enhanced fatty acid oxidation increasing expression levels of PPARα, CPT-1, and p-AMPK proteins in liver tissue, while simultaneously inhibited adipogenesis by reducing PPARγ and C/EBPα proteins in adipose tissue. Furthermore, NTU 101 supplementation positively modulated the composition of gut microbiota, notably increasing the abundance of Akkermansiaceae. This present study suggests that NTU 101 exerts anti-obesity effects by regulating gut microbiota, fatty acid oxidation, lipolysis and adipogenesis.

Stimulating intestinal GIP release reduces food intake and body weight in mice

ObjectiveGlucose dependent insulinotropic polypeptide (GIP) is well established as an incretin hormone, boosting glucose-dependent insulin secretion. However, whilst anorectic actions of its sister-incretin glucagon-like peptide-1 (GLP-1) are well established, a physiological role for GIP in appetite regulation is controversial, despite the superior weight loss seen in preclinical models and humans with GLP-1/GIP dual receptor agonists compared with GLP-1R agonism alone. MethodsWe generated a mouse model in which GIP expressing K-cells can be activated through hM3Dq Designer Receptor Activated by Designer Drugs (DREADD, GIP-Dq) to explore physiological actions of intestinally-released GIP. ResultsIn lean mice, Dq-stimulation of GIP expressing cells increased plasma GIP to levels similar to those found postprandially. The increase in GIP was associated with improved glucose tolerance, as expected, but also triggered an unexpected robust inhibition of food intake. Validating that this represented a response to intestinally-released GIP, the suppression of food intake was prevented by injecting mice peripherally or centrally with antagonistic GIPR-antibodies, and was reproduced in an intersectional model utilising Gip-Cre/Villin-Flp to limit Dq transgene expression to K-cells in the intestinal epithelium. The effects of GIP cell activation were maintained in diet induced obese mice, in which chronic K-cell activation reduced food intake and attenuated body weight gain. ConclusionsThese studies establish a physiological gut-brain GIP-axis regulating food intake in mice, adding to the multi-faceted metabolic effects of GIP which need to be taken into account when developing GIPR-targeted therapies for obesity and diabetes.

Corn Oligopeptide Alleviates Nonalcoholic Fatty Liver Disease by Regulating the Sirtuin Signaling Pathway.

Nonalcoholic fatty liver disease (NAFLD) represents the most prevalent type of chronic liver disease, spanning from simple steatosis to nonalcoholic steatohepatitis (NASH). Corn oligopeptide (CP) is a functional peptide known for its diverse pharmacological effects on metabolism. In this study, we evaluated the protective activity of CP against fatty liver disease. Oral administration of CP significantly reduced body weight gain by 2.95%, serum cholesterol by 22.54%, and liver injury, as evidenced by a reduction of 32.19% in serum aspartate aminotransferase (AST) and 49.10% in alanine aminotransferase (ALT) levels in mice subjected to a high-fat diet (HFD). In a streptozotocin/HFD-induced NASH mouse model, CP attenuated body weight gain by 5.11%, liver injury (with a 34.15% decrease in AST and 11.43% decrease in ALT), and, to some extent, liver inflammation and fibrosis. Proteomic analysis revealed the modulation of oxidative phosphorylation and sirtuin (SIRT) signaling pathways by CP. Remarkably, CP selectively inhibited the hepatic expression of mitochondrial SIRT3 and SIRT5 in both HFD and NASH models. In summary, CP demonstrates a preventive effect against metabolic-stress-induced NAFLD progression by modulating oxidative stress and the SIRT signaling pathway, suggesting the potential of CP as a therapeutic agent for the treatment of NAFLD and advanced-stage NASH.

WKYMVm ameliorates obesity by improving lipid metabolism and leptin signalling.

Obesity is a metabolic disorder that results from an imbalance of energy intake and consumption. As low-grade chronic inflammation caused by obesity can lead to various complications, it is important to develop effective treatments against obesity. In this study, we investigate the effects of WKYMVm, a strong anti-inflammatory agent, against obesity. Administration of WKYMVm into high fat diet (HFD)-induced obese mice significantly attenuated body weight gain, food intake and increased insulin sensitivity. HFD-induced hepatic steatosis and adipose tissue hypertrophy were also markedly ameliorated by WKYMVm. During the maturation of adipocytes, WKYMVm improves lipid metabolism by increasing lipolysis, adipogenesis, mitochondrial biogenesis and fat browning. WKYMVm administration also elicited a decrease in leptin levels, but an increase in leptin sensitivity via regulation of hypothalamic endoplasmic reticulum stress and the leptin receptor cascade. Taken together, our results show that WKYMVm ameliorates obesity by improving lipid metabolism and leptin signalling, suggesting that WKYMVm can be a useful molecule for the development of anti-obesity agents.

Therapeutic Potential of Diindolylmethane and Empagliflozin in DMBA-induced Breast Cancer: on Body Weight and Tumor Volume

Breast cancer remains a major global health concern, necessitating the exploration of novel therapeutic approaches. This study aimed to investigate the effects of Diindolylmethane (DIM) and Empagliflozin on body weight and tumor volume in a 7,12-Dimethylbenz[a]anthracene (DMBA)-induced breast cancer model. Female Sprague-Dawley rats were randomly divided into Five groups: Negative Control, Positive control, Standard treated, DIM + Empagliflozin lower doe(Treatment 1) and DIM + Empagliflozin higher dose (Treatment 2). The animals were monitored for changes in body weight, and tumor volume was measured using callipers. Our findings revealed that both DIM and Empagliflozin treatment significantly attenuated body weight gain compared to the Positive control group. Moreover, DIM and Empagliflozin exhibited substantial inhibitory effects on tumor volume. These results suggest that DIM and Empagliflozin may have potential therapeutic benefits in the management of breast cancer. DIM's anti-proliferative and pro-apoptotic properties, along with Empagliflozin's ability to modulate glucose metabolism, likely contribute to their observed effects on tumor growth. The synergistic effect of the combination treatment indicates a promising strategy for enhancing therapeutic efficacy. This study provides valuable insights into the potential use of DIM and Empagliflozin as adjunctive treatments for breast cancer. Further investigations are warranted to elucidate the underlying mechanisms and evaluate the long-term safety and efficacy of these agents. These findings contribute to the development of targeted therapeutic approaches and support the exploration of DIM and Empagliflozin in future clinical trials for breast cancer management.

Compound dark tea ameliorates obesity and hepatic steatosis and modulates the gut microbiota in mice.

Dark tea is a fermented tea that plays a role in regulating the homeostasis of intestinal microorganisms. Previous studies have found that dark tea can improve obesity and has a lipid-lowering effect. In this study, green tea, Ilex latifolia Thunb (kuding tea) and Momordica grosvenori (Luo Han Guo) were added to a new compound dark tea (CDT), to improve the taste and health of this beverage. High-fat diet-fed C57BL/6J mice were treated with low- (6 mg/mL) or high- (12 mg/mL) concentrations of CDT for 18 weeks to assess their effect on lipid metabolism. Our results suggest that low- and high-concentrations of CDT could reduce body weight by 15 and 16% and by 44 and 38% of body fat, respectively, by attenuating body weight gain and fat accumulation, improving glucose tolerance, alleviating metabolic endotoxemia, and regulating the mRNA expression levels of lipid metabolism-related genes. In addition, low concentrations of CDT were able to reduce the abundance of Desulfovibrio, which is positively associated with obesity, and increase the abundance of Ruminococcus, which are negatively associated with obesity. This study demonstrates the effect of CDT on ameliorating lipid metabolism and provides new insights into the research and development of functional tea beverages.

GABA and fermented litchi juice enriched with GABA promote the beneficial effects in ameliorating obesity by regulating the gut microbiota in HFD-induced mice.

Gamma-aminobutyric acid (GABA) dietary intervention is considered to have therapeutic potential against obesity. Microbial enrichment is an effective strategy to naturally and safely enhance GABA production in food. As litchi is "the king of GABA" in fruits, the retention or enrichment of its content during processing has been a key issue in the litchi industry. This study aimed to investigate the potential of GABA and fermented litchi juice enriched with GABA (FLJ) to protect against obesity in a high-fat diet (HFD) mouse model. Supplementation of GABA and FLJ displayed an anti-obesogenic effect by attenuating body weight gain, fat accumulation, and oxidative damage, and improving the serum lipid profile and hepatic function. Sequencing (16S rRNA) of fecal samples indicated that GABA and FLJ intervention displayed different regulatory effects on HFD-induced gut microbiota dysbiosis at different taxonomic levels. The microbial diversity, the relative abundance of Firmicutes and Bacteroidetes as well as the F/B ratio of GABA and FLJ groups were reversed compared to those of the HFD-induced mice. Our finding broadens the potential mechanisms by which GABA regulates gut flora in the amelioration of obesity and provides guidance for developing FLJ as a functional food to prevent obesity.

Dietary ingredient change induces a transient MyD88-dependent mucosal enteric glial cell response and promotes obesity

ABSTRACT Objective Consumption of a modern Western-type high-fat low-fiber diet increases the risk of obesity. However, how a host responds to such a diet, especially during the early period of dietary transition from a previous low-fat and fiber-rich diet, remains poorly explored. Methods Wild-type C57BL/6 mice were fed a normal chow diet or a high-fat diet. Enteric glial cell (EGC) activation was detected through quantitative real-time PCR (qRT-PCR), immunoblotting and immunohistology analysis. Fluorocitrate or genetic deletion of glial fibrillary acidic protein (GFAP)-positive glial-intrinsic myeloid differentiation factor 88 (Myd88) was used to inhibit EGC activation, and the effect of a high-fat diet on obesity was further investigated. The role of MYD88-dependent sensing of commensal products in adipocyte was observed to analyze the effect of obesity. Results A dietary shift from a normal chow diet to a high-fat diet in mice induced a transient early-phase emergence of a GFAP-positive EGC network in the lamina propria of the ileum, accompanied with an increase in glial-derived neurotrophic factor production. Inhibition of glial cell activity blocked this response. GFAP-positive glial Myd88 knockout mice gained less body weight after high-fat diet (HFD) feeding than littermate controls. In contrast, adipocyte deletion of Myd88 in mice had no effect on weight gain but instead exacerbated glucose intolerance. Furthermore, short-term fluorocitrate intervention during HFD feeding attenuated body weight gain. Conclusions Our findings indicate that EGCs are early responders to intestinal ecosystem changes and the GFAP-positive glial Myd88 signaling participates in regulating obesity.

Puerarin attenuates hepatic steatosis via G-protein-coupled estrogen receptor-mediated calcium and SIRT1 signaling pathways.

Puerarin, the major bioactive ingredient isolated from the root of Pueraria lobata (Willd.), attenuates body weight gain and reduces lipid levels in high-fat diet-induced obese mice; however, the underlying mechanism responsible for regulating lipid metabolism remains unclear. This study investigated the molecular mechanism(s) underlying the role of puerarin in regulating lipogenesis and lipolysis in human HepG2 cells. In this study, puerarin strongly inhibited the expression of fatty acid synthase (FASN) and sterol regulatory element binding protein 1c (SREBP-1c). Moreover, puerarin significantly induced the expression of adipose triglyceride lipase (ATGL), which is responsible for triacylglycerol hydrolase activity in cells. Puerarin enhanced 5' AMP-activated protein kinase (AMPK) activity, which is a central regulator of hepatic lipid metabolism. Furthermore, this AMPK activation could be mediated by sirtuin 1 (SIRT1) and calcium signaling pathways involved in G protein-coupled estrogen receptor (GPER) signaling. GPER blockage significantly reversed the effect of puerarin on lipid accumulation and the related signaling pathways. Docking studies showed that puerarin could bind in the GPER in a similar manner as GPER agonist G1. Our results suggest that puerarin can improve hepatic steatosis by activating GPER; it's signaling cascade sequentially induced calcium and SIRT1 signaling pathways. Thus, puerarin may be a potential therapeutic agent for the treatment of non-alcoholic fatty liver disease.

58-LB: Antidiabetic Effects of Pediococcus acidilactici pA1c on HFD-Induced Mice

Prediabetes (PreD) , which is associated with impaired glucose tolerance and fasting blood glucose, is a potential risk factor for type 2 diabetes mellitus (T2D) . Growing evidence suggests the role of the gastrointestinal microbiota in both PreD and T2D, which opens the possibility for a novel nutritional approach, based on probiotics, for improving glucose regulation and delaying disease progression of PreD to T2D. In this light, the present study aimed to assess the antidiabetic properties of Pediococcus acidilactici pA1c (pA1c) in a murine model of high-fat diet (HFD) -induced T2D. For that purpose, C57BL/6 mice were given HFD enriched with either probiotic (1×10E10 CFU/day) or placebo for 12 weeks. We determined body weight, fasting blood glucose, glucose tolerance, HOMA-IR and HOMA-β index, C-peptide, GLP-1, leptin, and lipid profile. We also measured hepatic gene expression (G6P, PEPCK, GCK, IL-1β, and IL-6) and ex-amined pancreatic and intestinal histology (% of GLP-1+ cells, % of goblet cells and villus length) . We found that pA1c supplementation significantly attenuated body weight gain, mitigated glucose dysregulation by reducing fasting blood glucose levels, glucose tolerance test, leptin levels, and insulin resistance, increased C-peptide and GLP-1 levels, enhanced pancreatic function, and improved intestinal histology. These findings indicate that pA1c improved HFD-induced T2D derived insulin resistance and intestinal histology, as well as protected from body weight increase. Together, our study proposes that pA1c may be a promising new dietary management strategy to improve metabolic disorders in PreD and T2D. Disclosure M. Cabello: None. M. Oneca: Employee; GENBIOMA APLICACIONES SL. M. J. Pajares: None. J. Ayo: Board Member; Genbioma Aplicaciones S. L., Employee; Genbioma Aplicaciones S. L. I. J. Encío: Other Relationship; Genbioma Aplicaciones SL. M. Araña: None. M. Barajas: None. Funding Government of Navarre (Ref 0011-1365-2020-000290) and the European Regional Development Fund (ERDF) . Maria Oneca is supported by Torres-Quevedo grants from the Spanish Ministry of Science and innovation (Ayudas para contratos Torres Quevedo PTQ2019-010384/AEI/10.13039/501100011033)

Progesterone Treatment Attenuates Body Weight Gain, Adiposity and Glycaemic Metabolism Damage in Obese Female Mice

Since the incidence of gestational diabetes is higher in obese women and those treated with progestogens during pregnancy, the aim of this study was to investigate the effect of progesterone (PG) on body composition, glucose metabolism and metabolic parameters in obese female mice. Post‐weaned female C57Bl/J6 were distributed into four groups: normocaloric control (NO‐CO, n=11), high fat and fructose control (HFF‐CO, n=10), normocaloric PG (NO‐PG, n=8) and high fat and fructose PG (HFF‐PG, n=9). The NO‐CO and NO‐PG mice fed a AING93 standard diet and the HFF‐CO and HFF‐PG fed a AIN93G diet added of lard (31%) and fructose (24%) during 10 weeks. In the 7th week, NO‐PG and HFF‐PG received an osmotic pump implant for constant infusion (0,25 mg/kg/d) of PG. All procedures were approved by the Ethics Committee of the School of Arts, Sciences and Humanities of University of Sao Paulo (003/2018). The daily food intake in grams was similar in all groups, but in terms of calories, the intake of the HFF‐CO and HFF‐PG (13.24+0.9 and 13.06+0.72 kcal/animal) groups was higher than NO‐CO and NO‐PG (9.22+0.2 and 9.53+0.53 kcal/animal) groups. The body weight gain was greater the HFF‐CO and HFF‐PG (11.52+0.94 and 9.61+0.85 g) groups compared to NO‐CO and NO‐PG (5.85+0.51 and 5.69+0.5 g) groups. Considering the final body weight of these animals (NO‐CO, 22.14+0.34 g; NO‐PG, 21.89+0.33 g; HFF‐CO, 28.76+0.59 g; HFF‐PG, 26.27+0.67 g) we observed not only the predicted increase in the weight of groups that received the HFF‐CO diet but also a lower increase in HFF‐PG group compared to HFF‐CO group. White adipose tissue fat pads (subcutaneous, SC‐WAT and retroperitoneal, RP‐WAT) increased significantly in the HFF‐CO group compared to NO‐CO and PG groups. In HFF‐PG, both WAT fat pads were greater compared to NO‐PG group, but only the WAT‐RP was greater compared to NO‐CO group. No differences were observed in interscapular brown adipose tissue and pancreas weight. On the other hand, the weight of liver was lower in HFF and HFF‐PG compared to NO‐CO and PG groups. No difference was found in the fasting glycaemia in the animals. From the results of the GTT and area under the curve (AUC) we observed that the HFF (23907+1304 mg/dL/120min) presented significantly higher AUC than NO‐CO and NO‐PG (17327+1042 and 18096+989 mg/dL/120min) groups. In addition, kITT of HFF‐CO (2.86+0.26 %/min) was significantly smaller compared to NO‐CO (4.23+0.56 %/min), NO‐PG (4.07+0.64 %/min) and HFF‐PG (3.89+0.4 %/min). Metabolic parameters measured in the indirect calorimetry during resting such as resting oxygen consumption, energy expenditure, respiratory exchange ratio, and the rates of carbohydrate and lipids oxidation did not differ among groups. In conclusion, the treatment with PG in a concentration that mimics those found in pregnancy attenuated body weight gain, adiposity and glycaemic metabolism damage observed in obese female mice.

Administration of Hookworm Excretory/Secretory Proteins Improves Glucose Tolerance in a Mouse Model of Type 2 Diabetes.

Diabetes is recognised as the world’s fastest growing chronic condition globally. Helminth infections have been shown to be associated with a lower prevalence of type 2 diabetes (T2D), in part due to their ability to induce a type 2 immune response. Therefore, to understand the molecular mechanisms that underlie the development of T2D-induced insulin resistance, we treated mice fed on normal or diabetes-promoting diets with excretory/secretory products (ES) from the gastrointestinal helminth Nippostrongylus brasiliensis. We demonstrated that treatment with crude ES products from adult worms (AES) or infective third-stage larvae (L3ES) from N. brasiliensis improved glucose tolerance and attenuated body weight gain in mice fed on a high glycaemic index diet. N. brasiliensis ES administration to mice was associated with a type 2 immune response measured by increased eosinophils and IL-5 in peripheral tissues but not IL-4, and with a decrease in the level of IL-6 in adipose tissue and corresponding increase in IL-6 levels in the liver. Moreover, treatment with AES or L3ES was associated with significant changes in the community composition of the gut microbiota at the phylum and order levels. These data highlight a role for N. brasiliensis ES in modulating the immune response associated with T2D, and suggest that N. brasiliensis ES contain molecules with therapeutic potential for treating metabolic syndrome and T2D.

Chronic High Phosphate Intake in Mice Affects Macronutrient Utilization and Body Composition.

In the last decades, dietary phosphate intake has increased due to a higher consumption of ultraprocessed food. This higher intake has an impact on body composition and health state. Recently, this study finds that a high chronic phosphate diet leads to no major renal alterations, but negatively affects parameters of bone health probably due to the chronic acid load. Here the effect of high phosphate consumption on parameters of energy metabolism is assessed. Healthy mature adult mice are fed for 1 year or 4 months with either a standard (0.6 % w/w) or a high phosphate (1.2 % w/w) diet. Males and females of two different genetic backgrounds are investigated. Mice feed the high phosphate diet show an attenuated body-weight gain, lower respiratory exchange ratio, decreased body fat mass, and increased lean-to-fat mass ratio. Moreover, the high phosphate diet leads to fasting hypoglycemia with no differences in the glucose response to an oral glucose tolerance test. Triglycerides and cholesterol in blood are similar independently of dietary phosphate content. However, 1-methylhistidine is lower in animals feed a chronic high phosphate intake. High phosphate diet attenuates body weight gain, but induces hypoglycemia and may alter muscle homeostasis.

Antidiabetic Effects of Pediococcus acidilactici pA1c on HFD-Induced Mice.

Prediabetes (PreD), which is associated with impaired glucose tolerance and fasting blood glucose, is a potential risk factor for type 2 diabetes mellitus (T2D). Growing evidence suggests the role of the gastrointestinal microbiota in both PreD and T2D, which opens the possibility for a novel nutritional approach, based on probiotics, for improving glucose regulation and delaying disease progression of PreD to T2D. In this light, the present study aimed to assess the antidiabetic properties of Pediococcus acidilactici (pA1c) in a murine model of high-fat diet (HFD)-induced T2D. For that purpose, C57BL/6 mice were given HFD enriched with either probiotic (1 × 1010 CFU/day) or placebo for 12 weeks. We determined body weight, fasting blood glucose, glucose tolerance, HOMA-IR and HOMA-β index, C-peptide, GLP-1, leptin, and lipid profile. We also measured hepatic gene expression (G6P, PEPCK, GCK, IL-1β, and IL-6) and examined pancreatic and intestinal histology (% of GLP-1+ cells, % of goblet cells and villus length). We found that pA1c supplementation significantly attenuated body weight gain, mitigated glucose dysregulation by reducing fasting blood glucose levels, glucose tolerance test, leptin levels, and insulin resistance, increased C-peptide and GLP-1 levels, enhanced pancreatic function, and improved intestinal histology. These findings indicate that pA1c improved HFD-induced T2D derived insulin resistance and intestinal histology, as well as protected from body weight increase. Together, our study proposes that pA1c may be a promising new dietary management strategy to improve metabolic disorders in PreD and T2D.

Protective role of intergenerational paternal resistance training on fibrosis, inflammatory profile, and redox status in the adipose tissue of rat offspring fed with a high-fat diet

AimsWe evaluated the role of intergenerational paternal exercise on fibrosis, inflammatory profile, and redox status in the adipose tissue of male rat offspring fed with high-fat diet (HFD) and explored to what extent programming affects the systemic metabolic profile. Main methodsAdult wistar rats were randomly divided into two groups: sedentary fathers and trained fathers (8 weeks of resistance training (RT), three times per week). The offspring were obtained by mating with sedentary females. Upon weaning, male offspring were divided into four groups (7 animals per group): offspring of sedentary fathers exposed to either a control diet (SFO-C) or a high-fat diet (SFO-HF); offspring of trained fathers exposed to a control diet (TFO-C) or a high-fat diet (TFO-HF). Key findingsPaternal RT was effective in attenuating body weight gain, adipocyte size, collagen deposition, as well as downregulating genes (CTGF, VEGF, C/EBPα SREBP1, MCP-1, and NF-kB), pro-inflammatory cytokine levels (Tumor Necrosis Factor alpha and Interleukin-1-beta), matrix metalloproteinase −2 activity, and ROS production in the epididymal adipose tissue of offspring fed with HFD (TFO-HF vs. SFO-HF; P < 0.05). Moreover, paternal RT increased adiponectin and superoxide dismutase (SOD) activity in the tissue. These beneficial effects were accompanied by the increase of antioxidant enzymes (SOD and α-Klotho), while decreasing pro-oxidant agents (F2-isoprostanes, protein carbonyls levels), and metabolic markers (insulin and leptin, HOMA-β, and HOMA-IR) in the offspring blood circulation. SignificanceOur findings reveal protective effects of intergenerational paternal RT on adipose tissue remodeling and metabolic health of offspring fed with HFD.

Efruxifermin, a long-acting Fc-fusion FGF21 analogue, reduces body weight gain but does not increase sympathetic tone or urine volume in Sprague Dawley rats.

Background and PurposeAnalogues of fibroblast growth factor 21 (FGF21) demonstrate diverse metabolic benefits in preclinical models of type 2 diabetes, dyslipidaemia and non‐alcoholic steatohepatitis (NASH), but clinical responses with different analogues are inconsistent. Efruxifermin is an Fc‐FGF21 fusion protein with prolonged half‐life and enhanced receptor affinity compared with native human FGF21. Efruxifermin is in clinical trials for the treatment of non‐alcoholic steatohepatitis.Experimental ApproachEfruxifermin was administered weekly to male and female Sprague Dawley rats for 4 or 26 weeks. Body and organ weights, macroscopic and microscopic pathology, clinical chemistry, blood cytology and serum and urine biomarkers were analysed to characterize the pharmacodynamics of efruxifermin and to investigate potential non‐clinical toxicities following chronic administration of supra‐pharmacological doses of efruxifermin.Key ResultsEfruxifermin significantly reduced body weight gain after 4 and 26 weeks, despite increasing food intake. Changes in tissue pathology, clinical chemistry and serum biomarkers generally appeared to be associated with weight loss, except for a significant decrease in urine volume in both males and females without perturbed electrolyte balance. Markers of sympathetic activation, urinary corticosterone and ratio of adrenal‐to‐body weight were unchanged.Conclusion and ImplicationsEfruxifermin attenuated body weight gain, consistent with other FGF21 analogues. In contrast to at least one other FGF21 analogue, efruxifermin decreased rather than increased urine volume. The absence of an increase in sympathetic tone in rats mirrors the unchanged salivary cortisol and systemic blood pressure following efruxifermin treatment in humans.

Gut microbiota mediates the alleviative effect of polar lipids-enriched milk fat globule membrane on obesity-induced glucose metabolism disorders in peripheral tissues in rat dams.

Obesity during pregnancy and lactation not only increases the incidence of metabolic disorders and gestational diabetes in mothers, but also programs adiposity and related metabolic diseases in offspring. The aim of this study was to investigate the effects of milk polar lipids on gut microbiota and glucose metabolism in high-fat diet (HFD)-fed rat dams. Sprague Dawley (SD) female rats were fed a HFD for 8 weeks to induce obesity, followed by HFD with or without oral administration of polar lipids-enriched milk fat globule membrane (MFGM-PL) at 400 mg/kg BW during pregnancy and lactation. At the end of lactation, fresh fecal samples of dams were collected, the gut microbiota was assessed, and the insulin-signaling protein expression in peripheral tissues (adipose tissue, liver and skeletal muscle) were measured. MFGM-PL supplementation attenuated body weight gain, ameliorated serum lipid profiles and improved insulin sensitivity in obese dams at the end of lactation. 16 S rDNA sequencing revealed that MFGM-PL increased the community richness and diversity of gut microbiota. The composition of gut microbiota was also changed after MFGM-PL supplementation as shown by an increase in the ratio of Bacteroidetes/Firmicutes and the relative abundance of Akkermansia, as well as a decrease in the relative abundance of Ruminococcaceae. The functional prediction of microbial communities by PICRUSt analysis showed that there were 7 KEGG pathways related to carbohydrate metabolism changed after MFGM-PL supplementation to HFD dams, including glycolysis/gluconeogenesis and insulin signaling pathway. Furthermore, MFGM-PL improved insulin signaling in the peripheral tissues including liver, adipose tissue and skeletal muscle. MFGM-PL supplementation during pregnancy and lactation improves the glucose metabolism disorders in HFD-induced obese dams, which may be linked to the regulation of gut microbiota induced by MFGM-PL.

Behavioral and Metabolic Effects of a Calorie-Restricted Cafeteria Diet and Oleuropein Supplementation in Obese Male Rats.

Diet-induced obesity models are widely used to investigate dietary interventions for treating obesity. This study was aimed to test whether a dietary intervention based on a calorie-restricted cafeteria diet (CAF-R) and a polyphenolic compound (Oleuropein, OLE) supplementation modified sucrose intake, preference, and taste reactivity in cafeteria diet (CAF)-induced obese rats. CAF diet consists of high-energy, highly palatable human foods. Male rats fed standard chow (STD) or CAF diet were compared with obese rats fed CAF-R diet, alone or supplemented with an olive tree leaves extract (25 mg/kg*day) containing a 20.1% of OLE (CAF-RO). Biometric, food consumption, and serum parameters were measured. CAF diet increased body weight, food and energy consumption and obesity-associated metabolic parameters. CAF-R and CAF-RO diets significantly attenuated body weight gain and BMI, diminished food and energy intake and improved biochemical parameters such as triacylglycerides and insulin resistance which did not differ between CAF-RO and STD groups. The three cafeteria groups diminished sucrose intake and preference compared to STD group. CAF-RO also diminished the hedonic responses for the high sucrose concentrations compared with the other groups. These results indicate that CAF-R diet may be an efficient strategy to restore obesity-associated alterations, whilst OLE supplementation seems to have an additional beneficial effect on sweet taste function.

Aerobic Physical Exercise Improves Exercise Tolerance and Fasting Glycemia Independent of Body Weight Change in Obese Females.

Obesity is associated with increased risk of several chronic diseases and the loss of disease-free years, which has increased the focus of much research for the discovery of therapy to combat it. Under healthy conditions, women tend to store more fat in subcutaneous deposits. However, this sexual dimorphism tends to be lost in the presence of comorbidities, such as type 2 diabetes mellitus (T2DM). Aerobic physical exercise (APE) has been applied in the management of obesity, however, is still necessary to better understand the effects of APE in obese female. Thus, we investigated the effect of APE on body weight, adiposity, exercise tolerance and glucose metabolism in female ob/ob mice. Eight-weeks-old female wild-type C57BL/6J and leptin-deficient ob/ob mice (Lepob) were distributed into three groups: wild-type sedentary group (Wt; n = 6), leptin-deficient sedentary group (LepobS; n = 5) and leptin-deficient trained group (LepobT; n = 8). The LepobT mice were subjected to 8 weeks of aerobic physical exercise (APE) at 60% of the maximum velocity achieved in the running capacity test. The APE had no effect in attenuating body weight gain, and did not reduce subcutaneous and retroperitoneal white adipose tissue (SC-WAT and RP-WAT, respectively) and interscapular brown adipose tissue (iBAT) weights. The APE neither improved glucose intolerance nor insulin resistance in the LepobT group. Also, the APE did not reduce the diameter or the area of RP-WAT adipocytes, but the APE reduced the diameter and the area of SC-WAT adipocytes, which was associated with lower fasting glycemia and islet/pancreas area ratio in the LepobT group. In addition, the APE increased exercise tolerance and this response was also associated with lower fasting glycemia in the LepobT group. In conclusion, starting APE at a later age with a more severe degree of obesity did not attenuate the excessive body weight gain, however the APE promoted benefits that can improve the female health, and for this reason it should be recommended as a non-pharmacological therapy for obesity.