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Introduction: It is well-known that different populations and animals, even experimental animals with the same rearing conditions, differ in their susceptibility to obesity. The disparity in gutmicrobiota could potentially account for the variation in susceptibility to obesity. However, the precise impact of gut microbiota on gut metabolites and its subsequent influence on susceptibility to obesity remains uncertain. Methods: In this study, we established obesity-prone (OP) and obesity-resistant (OR) mouse models by High Fat Diet (HFD). Fecal contents of cecum were examined using 16S rDNA sequencing and untargeted metabolomics. Correlation analysis and MIMOSA2 analysis were used to explore the association between gut microbiota and intestinal metabolites. Results: After a HFD, gutmicrobiota and gutmetabolic profiles were significantly different between OP and OR mice. Gut microbiota after a HFD may lead to changes in eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), a variety of branched fatty acid esters of hydroxy fatty acids (FAHFAs) and a variety of phospholipids to promote obesity. The bacteria g_Akkermansia (Greengene ID: 175696) may contribute to the difference in obesity susceptibility through the synthesis of glycerophosphoryl diester phosphodiesterase (glpQ) to promote choline production and the synthesis of valyl-tRNA synthetase (VARS) which promotes L-Valine degradation. In addition, gut microbiota may affect obesity and obesity susceptibility through histidinemetabolism, linoleic acid metabolism and protein digestion and absorption pathways. [ABSTRACT FROM AUTHOR]

Obesity is a multifactorial disorder that is remarkably heterogeneous. It presents itself in a variety of phenotypes that can be metabolically unhealthy or healthy, associate with no or multiple metabolic risk factors, gain extreme body weight (super-responders), as well as resist obesity despite the obesogenic environment (non-responders). Progression to obesity is ultimately linked to the overall net energy balance and activity of different metabolic fluxes. This is particularly evident from variations in fatty acids oxidation, metabolic fluxes through the pyruvate-phosphoenolpyruvate-oxaloacetate node, and extracellular accumulation of Krebs cycle metabolites, such as citrate. Patterns of fat accumulation with a focus on visceral and ectopic adipose tissue, microbiome composition, and the immune status of the gastrointestinal tract have emerged as the most promising targets that allow personalization of obesity and warrant further investigations into the critical issue of a wider and long-term weight control. Advances in understanding the biochemistry mechanisms underlying the heterogenous obesity phenotypes are critical to the development of targeted strategies to maintain healthy weight. [ABSTRACT FROM AUTHOR]

Male Sprague-Dawley rats consuming a moderately high-fat (MHF)-diet diverge into obesity-prone (OP) with hypertension and obesity-resistant. To study the temporal inter-relationships between body-weight, obesity-index, plasma lipid-profile, renal functional parameters and systolic-pressure alterations during 10-weeks feeding MHF or normal diet to male and female rats. Body-weight, obesity-index and systolic-pressure were measured weekly, while metabolic-cage and blood-sampling protocols were performed every other week. After 10-weeks, renal excretory responses to acute salt-loading and renal autoregulation were examined. The male-OP group had progressively increased body-weight, plasma-triglyceride and systolic-pressure from Weeks 2, 4 and 5, respectively, lower renal sodium-excretion at weeks 4–8 and finally, delayed excretory response to salt-loading and rightward and downward shifts in renal autoregulatory curves compared to all other groups. Feeding the MHF-diet in male-OP rats led to a greater weight-gain and adiposity followed by the development of atherogenic-hyperlipidaemia and persistently impaired pressure-natriuresis to induce hypertension. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?What is the role of the renal nerves in the development of obesity, hyperlipidaemia and hypertension during the long‐term feeding of a moderately high‐fat diet in male obesity‐prone rats?What is the main finding and its importance?The renal nerves play a prominent mediatory role, without influencing the establishment of visceral adiposity and atherogenic hyperlipidaemia, in the induction and progression of pressure natriuresis impairment and hypertension during the developmental period of diet‐induced obesity. Feeding a moderately high‐fat (MHF) diet in male Sprague–Dawley rats induces obesity, pressure natriuresis impairment and hypertension. This study investigated the role of the renal nerves in the impaired pressure natriuresis and hypertension caused by feeding a MHF diet. After collecting baseline data on day 0, 12 rats remained on a low‐fat diet (LF group) while the others were switched onto a MHF diet and diverged into obesity‐resistant (OR) or obesity‐prone (OP). After 4 weeks, half of the OR and OP rats underwent bilateral renal denervation (BRD) to generate four groups: OR, OR/BRD, OP and OP/BRD (n = 12). During 10 weeks, body weight, obesity index, systolic pressure and renal excretory function were measured regularly. After 10 weeks, renal excretory responses to acute salt loading and renal autoregulation were evaluated. The OP and OP/BRD groups had greater increases of body weight and obesity index during the dietary period compared to the other groups, and by week 10 their body weight (425.1 ± 7.2 and 411.9 ± 5.1 g) became considerably larger than that of the LF group (358.5 ± 6.2 g). Renal sodium excretion was reduced by ∼20% at week 4 in the OP and OP/BRD groups, while only the OP group had lower sodium excretion at weeks 6–8 and higher systolic pressure over weeks 5–10 than the other groups and its week 10 systolic pressure reached 138.1 ± 6.7 versus 123.6 ± 2.7 mmHg of the LF group. The OP group showed delayed renal excretory responses to salt loading with rightward and downward shifts in renal autoregulatory curves. Therefore, the renal nerves exert a main mediatory role in the development of pressure natriuresis impairment and hypertension as obesity is established due to the long‐term consumption of the MHF diet in male OP rats. [ABSTRACT FROM AUTHOR]

The rising rate of childhood overweight follows the increase in maternal obesity, since perinatal events impact offspring in a diversity of metabolic disorders. Despite many studies that have linked dietary consumption, overnutrition, or maternal obesity as the mediators of fetal metabolic programming, there are gaps regarding the knowledge about the contribution of different maternal phenotypes to the development of metabolic disturbances in offspring. This study aimed to investigate whether maternal high-fat diet (HFD) consumption without the development of the obese phenotype would protect offspring from metabolic disturbances. Female mice were fed standard chow diet or a HFD for 4 weeks before mating. HFD females were classified into obesity-resistant (OR) or obesity-prone (OP), according to weight gain. OP females presented with higher adiposity, fasting serum glucose and insulin, cholesterol and non-esterified fatty acid (NEFA). Newborn offspring from OP dams showed higher serum glucose and insulin and alteration in hepatic gene expression that may have contributed to the rise in hepatic fat content and decline of glycogen levels in the liver. Despite offspring from OR and OP females having showed similar growth after the day of delivery, offspring from OP females had higher caloric intake, fasting glucose, serum triglycerides and altered hepatic gene expression, as well as glucose and pyruvate intolerance and lower insulin sensitivity at d28 compared with offspring from OR females. Maternal pre-pregnancy serum glucose, insulin, and NEFA positively correlated with serum glucose and fat liver content and negatively correlated with hepatic glycogen in offspring. In conclusion, our results show that maternal resistance to diet-induced obesity partially protects offspring from early metabolic disturbances. [ABSTRACT FROM AUTHOR]

Introduction: It is well-known that different populations and animals, even experimental animals with the same rearing conditions, differ in their susceptibility to obesity. The disparity in gut microbiota could potentially account for the variation in susceptibility to obesity. However, the precise impact of gut microbiota on gut metabolites and its subsequent influence on susceptibility to obesity remains uncertain., Methods: In this study, we established obesity-prone (OP) and obesity-resistant (OR) mouse models by High Fat Diet (HFD). Fecal contents of cecum were examined using 16S rDNA sequencing and untargeted metabolomics. Correlation analysis and MIMOSA2 analysis were used to explore the association between gut microbiota and intestinal metabolites., Results: After a HFD, gut microbiota and gut metabolic profiles were significantly different between OP and OR mice. Gut microbiota after a HFD may lead to changes in eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), a variety of branched fatty acid esters of hydroxy fatty acids (FAHFAs) and a variety of phospholipids to promote obesity. The bacteria g_Akkermansia (Greengene ID: 175696) may contribute to the difference in obesity susceptibility through the synthesis of glycerophosphoryl diester phosphodiesterase (glpQ) to promote choline production and the synthesis of valyl-tRNA synthetase (VARS) which promotes L-Valine degradation. In addition, gut microbiota may affect obesity and obesity susceptibility through histidine metabolism, linoleic acid metabolism and protein digestion and absorption pathways., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wen, Luo, Qiu, Chen, Huang, Lv, Wang, Li, Tao, Yang, Li, He, He, Yang, Yu, Xiao, Zhao, Zou, Lu and Gu.)

Background: We have reported large differences in adiposity (fat mass/body weight) gain between rats fed a low-fat, high-starch diet, leading to their classification into carbohydrate "sensitive" and "resistant" rats. In sensitive animals, fat accumulates in visceral adipose tissues, leading to the suggestion that this form of obesity could be responsible for rapid development of metabolic syndrome.Objective: We investigated whether increased amylase secretion by the pancreas and accelerated starch degradation in the intestine could be responsible for this phenotype.Method: Thirty-two male Wistar rats (7-wk-old) were fed a purified low-fat (10%), high-carbohydrate diet for 6 wk, in which most of the carbohydrate (64% by energy) was provided as corn starch. Meal tolerance tests of the Starch diet were performed to measure glucose and insulin responses to meal ingestion. Indirect calorimetry combined with use of 13C-labelled dietary starch was used to assess meal-induced changes in whole body and starch-derived glucose oxidation. Real-time polymerase chain reaction was used to assess mRNA expression in pancreas, liver, white and brown adipose tissues, and intestine. Amylase activity was measured in the duodenum, jejunum, and ileum contents. ANOVA and regression analyses were used for statistical comparisons.Results: "Resistant" and "sensitive" rats were separated according to adiposity gain during the study (1.73% ± 0.20% compared with 4.35% ± 0.36%). Breath recovery of 13CO2 from 13C-labelled dietary starch was higher in "sensitive" rats, indicating a larger increase in whole body glucose oxidation and, conversely, a larger decrease in lipid oxidation. Amylase mRNA expression in pancreas, and amylase activity in jejunum, were also higher in sensitive rats.Conclusion: Differences in digestion of starch can promote visceral fat accumulation in rats when fed a low-fat, high-starch diet. This mechanism may have important implications in human obesity. [ABSTRACT FROM AUTHOR]

The study was designed to investigate the possible mechanisms of hepatic microRNAs (miRs) in regulating local thyroid hormone (TH) action and ultimately different propensities to high-fat diet (HFD)-induced obesity. When obesity-prone (OP) and obesity-resistant (OR) mice were fed HFD for 7 weeks, OP mice showed apparent hepatic steatosis, with significantly higher body weight and lower hepatic TH receptor b (TRb) expression and type 1 deiodinase (DIO1) activity than OR mice. Next-generation sequencing technology revealed that 13 miRs in liver were dysregulated between the two phenotypes, of which 8 miRs were predicted to target on Dio1 or TRb. When mice were fed for 17 weeks, OR mice had mild hepatic steatosis and increased Dio1 and TRb expression than OP mice, with downregulation of T3 target genes (including Srebp1c, Acc1, Scd1 and Fasn) and upregulation of Cpt1α, Atp5c1, Cox7c and Cyp7a1. A stemloop qRT-PCR analysis confirmed that the levels of miR-383, miR-34a and miR-146b were inversely correlated with those of DIO1 or TRb. Down-regulated expression of miR-383 or miR-146b by miR-383 inhibitor (anti-miR-383) or miR-146b inhibitor (anti-miR-146b) in free fatty acid-treated primary mouse hepatocytes led to increased DIO1 and TRb expressions, respectively, and subsequently decreased cellular lipid accumulation, while miR-34a inhibitor (anti-miR-34a) transfection had on effects on TRb expression. Luciferase reporter assay illustrated that miR-146b could directly target TRb 3'untranslated region (3'UTR). These findings suggested that miR-383 and miR-146b might play critical roles in different propensities to diet-induced obesity via targeting on Dio1 and TRb, respectively. [ABSTRACT FROM AUTHOR]

Lingual fatty acid receptors ( i.e. CD36) mediate the orosensory perception of fat/fatty acids and may contribute to the susceptibility to develop obesity. The current study tested the hypothesis that fat/fatty acid preference in obesity-prone (OP, Osborne-Mendel) and obesity-resistant (OR, S5B/Pl) rats is mediated by nutritional status and lingual CD36. To determine if nutritional status affected linoleic acid (LA) preference in OP and OR rats, rats were either fasted overnight or fed a high fat diet (60% kcal from fat). In OR rats, fasting increased the preference for higher concentrations of LA (1.0%), while consumption of a high fat diet decreased LA preference. In OP rats, fasting increased the preference for lower concentrations of LA (0.25%), however high fat diet consumption did not alter LA preference. To determine if lingual CD36 mediated the effects of an overnight fast on LA preference, the expression of lingual CD36 mRNA was assessed and the effect of lingual application of CD36 siRNA on LA preference was determined. Fasting increased lingual CD36 mRNA expression in OR rats, but failed to alter lingual CD36 mRNA in OP rats. Following an overnight fast, application of lingual CD36 siRNA led to a decrease in LA preference in OR, but not OP rats. Lingual application of CD36 siRNA was also used to determine if lingual CD36 mediated the intake and preference for a high fat diet in OP and OR rats. CD36 siRNA decreased the preference and intake of high fat diet in OR rats, but not OP rats. The results from this study suggest that the dysregulation of lingual CD36 in OP rats is a potential factor leading to increased fat intake and fat preference and an enhanced susceptibility to develop obesity. [ABSTRACT FROM AUTHOR]

Background: Susceptibility to obesity is associated with a notable inter-individual variation. The aim of the present study was to compare the effectiveness of sleeve gastrectomy (SG) on weight loss and metabolic profile in obesity-prone (OP) rats vs animals that are non-susceptible to obesity (NSO). Methods: Young male Wistar rats ( n = 101) were put in a diet-induced obesity (DIO) programme with ad libitum access to a high-fed diet (HFD) during 12 months. Body weight and food intake were regularly registered. Thereafter, rats were ranked by final body weight to identify the obesity-prone (OP) ( n = 13) and non-susceptible to obesity (NSO) ( n = 14) animals. OP and NSO rats were submitted to surgical interventions (sham operation, SG and pair-fed to the amount of food eaten by sleeve-gastrectomized rats). Body weight, food intake, energy expenditure, body temperature, fat pads weight, and metabolic profiling were analysed 4 weeks after surgical or dietary interventions. Results: SG in both OP and NSO rats decreased body weight as compared to sham and pair-fed groups ( P < 0.05), mainly due to reductions in subcutaneous and perirenal fat mass ( P < 0.001). Total weight loss achieved in sleeve-gastrectomized OP and NSO rats was higher than that of pair-fed ones ( P < 0.05), showing that the SG effect goes beyond caloric restriction. In this regard, sleeve-gastrectomized rats exhibited significantly ( P < 0.05) increased basal rectal temperature together with upregulated brown adipose tissue Ucp-1 protein expression levels. A significant ( P < 0.05) improvement in insulin sensitivity was also observed in both OP and NSO animals that underwent SG as compared with pair-fed counterparts. Conclusion: Our findings provide the first evidence that obesity-prone rats also benefit from surgery responding effectively to SG, as evidenced by the significant body weight reduction and the metabolic profile improvement. [ABSTRACT FROM AUTHOR]

The current experiment tested the hypothesis that consumption of a high-fat diet (HFD) would differentially affect metabolic parameters in obesity-prone Osborne-Mendel (OM) and obesity-resistant S5B/Pl (S5B) rats. In OM rats consuming a HFD, an increase in HFD intake, body mass, and percent fat mass, and a HFD-induced decrease in metabolic rate and energy expenditure were demonstrated. In S5B rats consuming a HFD, no change in percent body fat or HFD intake was demonstrated and HFD increased metabolic rate and energy expenditure. To assess whether HFD differentially altered skeletal muscle markers of metabolism inOMand S5B rats, the expression of the transporters, CD36 and GLUT4, and the energy sensors, AMPK and PPARγ, in the gastrocnemius muscle was measured. Oxidation and lipid accumulation in the gastrocnemius muscle was histologically determined. Consumption of a HFD decreased phosphorylated AMPK and PPARγ expression in the skeletal muscle of obesity-prone OM rats. Lipid accumulation in skeletal muscle was significantly higher in OM rats fed a HFD. Overall, these data suggest that the differential response to HFD on metabolic rate, energy expenditure, and phosphorylated AMPK and PPARγ in OM and S5B rats, may partially account for differences in the susceptibility to develop obesity. [ABSTRACT FROM AUTHOR]

Background The exact mechanism for different propensities to obesity when consuming a high-fat diet (HFD) is largely unknown. Thyroid hormone (TH) is an important modulator of energy homeostasis and body weight. Objective The present study aimed to find the potential mechanisms of TH in the development of obesity-prone (OP) and obesity-resistant (OR) mice after short-term and long-term HFD feeding. Methods C57Bl/6 male mice were randomly divided into two groups: a low-fat diet (LFD) group and an HFD group. In the 7th week, HFD-fed mice were classified as OP or OR according to upper and lower tertiles of body weight. Half of the mice were sacrificed at this time point and the remaining mice were kept on feeding and sacrificed in the 27th week. Indirect calorimetry was performed. At harvest, serum was used for ELISA assays and oxidative stress biomarkers determination. Tissues were dissected for deiodinases activity and relative mRNA expression determination, as well as antioxidant capacity evaluation. Results In the 7th week, OP mice showed a significant body weight gain, decreased energy expenditure (EE), normal circulating TH levels, and activated HPT axis, whereas OR mice had normal body weight and maintained T 3 levels only through enhancing hepatic D1 activity. In the 27th week, OR mice gained more body weight than LFD mice accompanied by an activation of HPT axis and decreased hepatic deiodination. Genes involved in TH production were down-regulated in OP mice and up-regulated in OR mice. Changes in deiodinases activity and thyroid function were related with redox status in specific tissues. Furthermore, OP mice had more serious hepatic steatosis than OR mice, with up-regulation of T 3 target genes ( e.g. Srebp1c, Acc1, Fasn) involved in lipid synthesis and down-regulation of Pgc1α , Cyp7a1 and Cpt1α . Conclusions HPT axis function and deiodinases activity might be involved in different propensities to obesity and the ability of OR mice to resist obesity was limited. [ABSTRACT FROM AUTHOR]

Obesity-prone (OP) individuals have a significant predisposition to obesity and diabetes. Previously, we have found that OP individuals, despite being normal in weight and BMI, have already exhibited diabetes-related DNA methylation signatures. However, the underlying mechanisms remain obscure. Here we determined the effects of gut microbiota on DNA methylation and investigated the underlying mechanism from microbial-derived short-chain fatty acids (SCFAs). Diabetes-related DNA methylation loci were screened and validated in a new OP cohort. Moreover, the OP group was revealed to have distinct gut microbiota compositions, and fecal microbiota transplantation (FMT) demonstrated the role of gut microbiota in inducing diabetes-related DNA methylations and glucolipid disorders. UPLC-ESI-MS/MS analysis indicated a significantly lower level of total fecal SCFAs in the OP group. The gut microbiota from OP subjects yielded markedly decreased total SCFAs, while notably enriched propionate. Additionally, propionate was also identified by variable importance in projection (VIP) score as the most symbolic SCFAs of the OP group. Further cellular experiments verified that propionate could induce hypermethylation at locus cg26345888 and subsequently inhibit the expression of the target gene DAB1 , which was crucially associated with clinical vitamin D deficiency and thus may affect the development and progression of diabetes. In conclusion, our study revealed that gut microbiota-derived propionate induces specific DNA methylation, thus predisposing OP individuals to diabetes. The findings partially illuminate the mechanisms of diabetes susceptibility in OP populations, implying gut microbiota and SCFAs may serve as promising targets both for clinical treatment and medication development of diabetes. [Display omitted] [ABSTRACT FROM AUTHOR]

Obesityprone (OP) rodents are used as models of human obesity predisposition. The goal of the present study was to identify preexisting defects in energy expenditure components in OP rats. Two studies were performed. In the first one, male Wistar rats (n 48) were fed a high-carbohydrate diet (HCD) for 3 wk and then a high-fat diet (HFD) for the next 3 wk. This study showed that adiposity gain under HCD was 2.9-fold larger in carbohydrate-sensitive (CS) than in carbohydrate- resistant (CR) rats, confirming the concept of "carbohydratesensitive" rats. Energy expenditure (EE), respiratory quotient (RQ), caloric intake (CI), and locomotor activity measured during HFD identified no differences in EE and RQ between fat-resistant (FR) and fat-sensitive (FS) rats, and indicated that obesity developed in FS rats only as the result of a larger CI not fully compensated by a parallel increase in EE. A specific pattern of spontaneous activity, characterized by reduced activity burst intensity, was identified in FS rats but not in CS ones. This mirrors a previous observation that under HCD, CS but not FS rats, exhibited bursts of activity of reduced intensity. In a second study, rats were fed a HFD for 3 wk, and the components of energy expenditure were examined by indirect calorimetry in 10 FR and 10 FS rats. This study confirmed that a low basal EE, reduced thermic effect of feeding, defective postprandial energy partitioning, or a defective substrate utilization by the working muscle are not involved in the FS phenotype. [ABSTRACT FROM AUTHOR]

Differential sensing of dietary fat and fatty acids by the oral cavity is proposed to regulate the susceptibility to obesity. In the current experiments, animals that differ in their susceptibility to obesity were used to investigate the influence of the oral cavity on the preference for the polyunsaturated fatty acid, linoleic acid. In experiment 1, the preference for differing concentrations of linoleic acid was determined in obesity-prone Osborne-Mendel (OM) and obesity-resistant S5B/Pl (S5B) rats. The preference threshold for linoleic acid was lower in S5B rats, compared with OM rats. To determine whether differences in linoleic acid preference threshold were related to innate strain differences in the fatty acid receptors on the tongue, the expression of GPR120, GPR40, and CD36 on the circumvallate papillae were assessed in OM and S5B rats. Results indicated that the expression of CD36, GPR40, and GPR120 did not differ between these two strains. Numerous studies have examined the role of CD36 on fat intake; therefore, in experiment 3, RNA interference was used to decrease the expression of CD36 on the tongues of OM and S5B rats, and the effect of decreased CD36 expression on linoleic acid preference was determined. CD36 siRNA attenuated linoleic acid preference for the most preferred concentration in both OM and S5B rats. Overall, these data indicate that there are innate differences in the preference threshold for linoleic acid in obesity-prone and obesity-resistant rats. Experimentally reducing the expression of CD36 on the circumvallate papillae attenuated the preference for linoleic acid in both strains. [ABSTRACT FROM AUTHOR]

Overweight and/or obesity are known risk factors for postmenopausal breast cancer. More recently increased body weight has also been associated with poor prognosis for premenopausal breast cancer. This relationship has primarily been identified through epidemiological studies. Additional information from in vitro studies has also been produced in attempts to delineate mechanisms of action for the association of obesity and body weight and breast cancer. This approach has identified potential growth factors such as insulin, leptin, estrogen and IGF-I which are reported to be modulated by body weight changes. However, in vitro studies are limited in scope and frequently use non-physiological concentrations of growth factors, while long follow-up is needed for human studies. Preclinical animal models provide an intermediary approach to investigate the impact of body weight and potential growth factors on mammary/breast tumor development and progression. Here results of a number of studies addressing this issue are presented. In the majority of the studies either genetically-obese or diet-induced obese rodent models have been used to investigate spontaneous, transgenic and carcinogen-induced mammary tumor development. To study tumor progression the major focus has been allograft studies in mice with either genetic or dietary-induced obesity. In general, obesity has been demonstrated to shorten mammary tumor latency and to impact tumor pathology. However, in rodents with defects in leptin and other growth factors the impact of obesity is not as straightforward. Future studies using more physiologically relevant obesity models and clearly distinguishing diet composition from body weight effects will be important in continuing to understand the factors associated with body weight’s impact on mammary/breast cancer development and progression. [ABSTRACT FROM AUTHOR]

Background: The gastrointestinal tract (GI) is important for detection and transport of consumed nutrients and has been implicated in susceptibility to diet-induced obesity in various rat strains. Aims: The current studies investigated the regulation of CD36, a receptor which facilitates uptake of long-chain fatty acids, in the GI tract of obesity-prone Osborne-Mendel and obesity-resistant S5B rats fed a high-fat diet. Methods: Osborne-Mendel and S5B rats consumed a high-fat diet (HFD, 55 % kcal from fat) or a low-fat diet (10 % kcal from fat) for either 3 or 14 days. CD36 messenger RNA (mRNA) levels were measured from circumvallate papillae of the tongue and from duodenal enterocytes. Results: In Osborne-Mendel rats, consumption of HFD for 3 and 14 days led to an increase in CD36 mRNA on circumvallate papillae and in duodenal enterocytes. CD36 mRNA levels were positively correlated with body weight gain and kilocalories consumed at 3 days. In S5B rats, consumption of HFD for 3 days did not alter CD36 mRNA levels on circumvallate papillae or in the duodenum. Duodenal CD36 levels were elevated in S5B rats following 14 days of HFD consumption. CD36 mRNA levels in the duodenum were positively correlated with body weight gain and kilocalories consumed at 14 days. Conclusions: These data support the differential sensing of nutrients by two regions of the GI tract of obesity-prone and obesity-resistant rats consuming HFD and suggest a role for CD36 in the strain-specific susceptibility to obesity. [ABSTRACT FROM AUTHOR]

Background: The gastrointestinal tract is important in the regulation of food intake, nutrient sensing and nutrient absorption. Obesity-prone Osborne-Mendel (OM) rats are less sensitive to the satiating effects of a duodenal infusion of fatty acids than obesity-resistant S5B/Pl (S5B) rats, suggesting that the gastrointestinal tract differentially senses the presence of fat in these two strains. A microarray analysis was conducted to identify genes that were differentially expressed in the duodenal enterocytes of OM and S5B rats. Aims: The present experiment evaluated the expression of olfactory receptors in the duodenal enterocytes of OM and S5B rats. It was hypothesized that olfactory receptors present in the duodenum of OM and S5B rats would be differentially regulated by the intake of a high fat diet. Methods: The mRNA levels of four olfactory receptors (Olr1744, Olr50, Olr124, Olr1507) were assessed from the duodenal enterocytes of OM and S5B rats consuming a high fat diet for 14 days. Results: The duodenal mRNA levels of Olr1744, Olr124 and Olr1507 were significantly elevated in OM rats fed the high fat diet, but not S5B rats. No differences in the expression of Olr50 receptor mRNA were detected. Conclusions: These data suggest that several olfactory receptors present in the duodenum are selectively regulated by high fat diet intake in obesity-prone OM rats. Therefore, these receptors may play a role in the sensing and regulation of dietary fat, and may be important for the individual susceptibility to obesity in these two strains. [ABSTRACT FROM AUTHOR]

Abstract: Obese humans and animals exhibit reduced functioning of the dopamine (DA) system in the nucleus accumbens (NAc). The question addressed here is whether this change in NAc DA can be detected in Sprague–Dawley rats that are prone to obesity on a fat-rich diet but still at normal body weight. Rats were subgrouped as “obesity-prone” (OP) or “obesity-resistant” (OR), based on their weight gain during 5days of access to a high-fat diet, and were then shifted to a lower-fat chow diet before microdialysis testing was performed. The OP rats compared to OR rats exhibited markedly reduced basal levels of DA in the NAc. After a high-fat challenge meal, both OP and OR rats showed a significant increase in extracellular DA and its metabolites; however, the NAc DA of the OP rats still remained at reduced levels. Also, the increase in DA and metabolite levels observed in OR rats after systemic administration of a fat emulsion was not evident in the OP rats, which instead showed no change in DA and a decrease in its metabolites. These results demonstrate, first, that fat can stimulate accumbal DA release and, second, that outbred rats prone to overeating and becoming obese on a palatable, fat-rich diet exhibit reduced signaling in the mesolimbic DA system while still at normal weight, suggesting that it may be causally related to their excess consummatory behavior. [ABSTRACT FROM AUTHOR]

Background:Osborne-Mendel (OM) rats are prone to obesity when fed a high-fat diet, whereas S5B/Pl (S5B) rats are resistant to diet-induced obesity when fed the same diet. OM rats have a decreased satiation response to fatty acids infused in the gastrointestinal tract, compared to S5B rats. One possible explanation is that OM rats are less sensitive to the satiating hormone, glucagon-like peptide 1 (GLP-1). GLP-1 is produced in the small intestine and is released in response to a meal. The current experiments examined the role of GLP-1 in OM and S5B rats.Methods:Experiment 1 examined preproglucagon mRNA expression in the ileum of OM and S5B rats fed a high-fat (55% kcal) or low-fat (10% kcal) diet. Experiment 2 investigated the effects of a 2 h high-fat meal after a 24 h fast in OM and S5B rats on circulating GLP-1 (active) levels. Experiment 3 examined the effects of exendin-4 (GLP-1 receptor agonist) administration on the intake of a high-fat or a low-fat diet in OM and S5B rats.Results:Preproglucagon mRNA levels were increased in the ileum of OM rats compared to S5B rats and were increased by high-fat diet in OM and S5B rats. OM and S5B rats exhibited a similar meal-initiated increase in circulating GLP-1 (active) levels. Exendin-4 dose dependently decreased food intake to a greater extent in S5B rats compared to OM rats. The intake of low-fat diet, compared to the intake of high-fat diet, was more sensitive to the effects of exendin-4 in these strains.Conclusions:These results suggest that though OM and S5B rats have similar preproglucagon mRNA expression in the ileum and circulating GLP-1 levels, OM rats are less sensitive to the satiating effects of GLP-1. Therefore, dysregulation of the GLP-1 system may be a mechanism through which OM rats overeat and gain weight. [ABSTRACT FROM AUTHOR]

Abstract: Obese individuals often suffer from depression. The olfactory bulbectomy (OBX) model is an animal model of depression that produces behavioral, physiological, and neurochemical alterations resembling clinical depression. The OBX model was employed to assess depression-related changes in food intake in obesity-prone, Osborne–Mendel (OM) rats and obesity-resistant, S5B/Pl rats. OBX increased food intake in OM rats beginning 7 days following surgery, however, OBX did not alter food intake in S5B/Pl rats at any time point. Fourteen days following surgery, OBX significantly increased locomotor activity (total lines crossed and rears) in the openfield test in OM and S5B/Pl rats. Fifteen days following surgery, prepro-neuropeptide Y (NPY) mRNA levels were significantly increased in the hypothalamus of bulbectomized OM rats and in the medial nucleus of the amygdala of bulbectomized OM and S5B/Pl rats. OBX decreased NPY Y2 receptor mRNA levels in the hypothalamus and medial nucleus of the amygdala in OM rats, while increasing NPY Y2 receptor mRNA levels in the medial nucleus of the amygdala of S5B/Pl rats. These data indicate that though both obesity-prone and obesity-resistant strains were susceptible to the locomotor effects of OBX, food intake and hypothalamic prepro-NPY mRNA were only increased in OM rats. Therefore, strain specific alterations in hypothalamic NPY may account for increased food intake in the obesity-prone rats following OBX, and suggests a potential mechanism to explain the comorbidity of obesity and depression. [Copyright &y& Elsevier]

Objective:To characterize and compare three obesity-prone inbred strains, AKR/J, DBA/2J and C57BL/6J, to three control strains, C3H/HeJ, BALB/cByJ and C57L/J, selected based on their normal eating patterns and moderate weight gain on high-calorie diets.Methods and procedures:These six strains were examined at 5 weeks of age while still of normal body weight, and they were maintained for 1 day or 3 weeks on different feeding paradigms with macronutrient diets. Measurements were taken of macronutrient intake, body weight and body fat accrual, circulating hormones and metabolites, and the hypothalamic peptide, galanin.Results:The three control strains each selected a balanced diet with 50% carbohydrate and 15–25% fat when given a choice of macronutrients, and they had similar, normal range of scores for the measures of body weight, adiposity, the hormones, insulin and leptin, and the metabolites, glucose and triglycerides. When compared to this control baseline, the obesity-prone strains with similar total caloric intake to controls selected a diet with significantly more fat (30–40%) and less carbohydrate (<40%). They also had greater adiposity, with the largest differences detected for the AKR/J and DBA/2J strains. These two obesity-prone strains compared to control strains had elevated levels of insulin and leptin. They also had higher triglyceride levels and increased expression and levels of galanin in the hypothalamic paraventricular nucleus. A very different pattern was detected in the obesity-prone C57BL/6J strain, which exhibited a stronger preference for protein as well as fat, normal levels of insulin, leptin and triglycerides, hyperglycemia relative to all other strains, and a small increase in galanin.Conclusion:These comparisons to control strains revealed a distinct phenotype in the two obesity-prone strains, AKR/J and DBA/2J, which is very similar to that described in obesity-prone, outbred rats. They also identified a clearly different phenotype in the obesity-prone C57BL/6J strain.International Journal of Obesity (2006) 30, 50–59. doi:10.1038/sj.ijo.0803110; published online 11 October 2005 [ABSTRACT FROM AUTHOR]

Abstract: Unpredictable stressors have been used to assess the effect of stress on energy metabolism in obesity-prone (C57BL6J) and obesity-resistant (AJ) mice. Mice were exposed for 25 days to a stress protocol. Both strains of mice were divided into groups of control and stressed mice, which had access to either a high-fat or a high-carbohydrate diet. Twenty-four hours after the last session of stress, mice were sacrificed for blood and brain collections. Insulin, corticosterone, and glucose concentrations in plasma were measured, and expressions of corticotropin-releasing factor (CRF) in the paraventricular hypothalamic nucleus (PVH) and the central amygdala (CeA) were determined by in situ hybridization. Stressed mice in all groups had lower body fat contents than control mice, and all mice fed with the high-fat diet had heavier retroperitoneal and inguinal fat pads than mice fed with carbohydrate. CRF mRNA level in the CeA was lower in B6 mice than in AJ mice. Stressed mice had a lower expression of CRF in the CeA than control mice. In conclusion, chronic stress reduces body fat content in obesity-prone as well as in obesity-resistant mice. [Copyright &y& Elsevier]

We investigated whether fuel metabolism prior to high-fat feeding differs in outbred Sprague–Dawley rats either prone or resistant to diet-induced obesity. Chow-fed rats were deprived of food, and blood was collected 12, 18, and 24 h later. Rats were then fed a high-fat diet ad libitum for up to 4 weeks to assess weight gain. Blood samples were analyzed for a variety of metabolic fuels and hormones. Only fasting plasma triglyceride concentrations showed a positive correlation with the weight gain during the high-fat feeding period, with concentrations after 18 h of fasting showing the most consistent relationship to weight gain. Body weights and fat pad weights did not correlate with fasting plasma triglyceride concentrations before high-fat feeding. The amount of 14CO2 recovered from gavaged [14C]palmitic acid in chow-fed rats negatively correlated with weight gain during the subsequent period of high-fat feeding. These results show that there are preexisting differences in fat catabolism that may underlie differential susceptibility to diet-induced obesity; in particular, fasting levels of plasma triglycerides and fatty acid oxidation may be early predictive markers for this susceptibility. [Copyright &y& Elsevier]

• Between-network connectivity (BNC) assessed in adults prone or resistant to obesity. • Increased basal ganglia and dorsolateral prefrontal cortex BNC in obesity-prone group. • May reflect disrupted balance between goal-directed and habitual control systems. Investigating intrinsic brain functional connectivity may help identify the neurobiology underlying cognitive patterns and biases contributing to obesity propensity. To address this, the current study used a novel whole-brain, data-driven approach to examine functional connectivity differences in large-scale network interactions between obesity-prone (OP) and obesity-resistant (OR) individuals. OR (N = 24) and OP (N = 25) adults completed functional magnetic resonance imaging (fMRI) during rest. Large-scale brain networks were identified using independent component analysis (ICA). Voxel-specific between-network connectivity analysis assessed correlations between ICA component time series' and individual voxel time series, identifying regions strongly connected to many networks, i.e., "hubs". Significant group differences in between-network connectivity (OP vs. OR; FDR-corrected) were observed in bilateral basal ganglia (left: q = 0.009; right: q = 0.010) and right dorsolateral prefrontal cortex (dlPFC; q = 0.026), with OP>OR. Basal ganglia differences were largely driven by a more strongly negative correlation with a lateral sensorimotor network in OP, with dlPFC differences driven by a more strongly negative correlation with an inferior visual network in OP. Greater between-network connectivity was observed in the basal ganglia and dlPFC in OP, driven by stronger associations with lateral sensorimotor and inferior visual networks, respectively. This may reflect a disrupted balance between goal-directed and habitual control systems and between internal/external monitoring processes. [ABSTRACT FROM AUTHOR]

• We identified sex and region-specific differences in perineuronal net intensity following exposure to dietary high fat. • Genetic susceptibility to obesity influences perineuronal net intensity, such that obesity-prone rats have similar changes in perineuronal net intensity to Sprague Dawley rats following exposure to a high fat diet. • There are opposing effects of high fat diet-induced changes in perineuronal net intensity between obesity-prone and obesity-resistant rat populations. Perineuronal nets (PNNs) are specialized extracellular matrix structures that primarily surround fast-spiking parvalbumin (PV)-containing interneurons within the PFC. They regulate PV neuron function and plasticity to maintain cortical excitatory/inhibitory balance. For example, reductions in PNN intensity are associated with reduced local inhibition and enhanced pyramidal neuron firing. We previously found that exposure to dietary high fat reduced PNN intensity within the PFC of male Sprague-Dawley (SD) rats. However, how high fat affects PNNs in the PFC of females or in obesity-vulnerable vs. –resistant models is unknown. Therefore, we gave male and female SD, selectively bred obesity-prone (OP), and obesity-resistant rats (OR) free access to standard lab chow or 60% high fat for 21 days. We then measured the number of PNN positive cells and PNN intensity (determined by Wisteria floribunda agglutinin [WFA] staining) as well as the number of PV positive neurons using immunohistochemistry. We found sex and region-specific effects of dietary high fat on PNN intensity, in the absence of robust changes in cell number. Effects were comparable in SD and OP but differed in OR rats. Specifically, high fat reduced PNN intensities in male SD and OP rats but increased PNN intensities in female SD and OP rats. In contrast, effects in ORs were opposite, with males showing increases in PNN intensity and females showing a reduction in intensity. Finally, these effects were also region specific, with diet-induced reductions in PNN intensity found in the prelimbic PFC (PL-PFC) and ventral medial orbital frontal cortex (vmOFC) of SD and OP males in the absence of changes in the infralimbic PFC (IL-PFC), and increases in PNN intensity in the IL-PFC of SD and OP females in the absence of changes in other regions. These results are discussed in light of roles PNNs may play in influencing PFC neuronal activity and the differential role of these sub-regions in food-seeking and motivation. [ABSTRACT FROM AUTHOR]

Obesity is characterized with high heterogeneity due to genetic abnormality, energy imbalance, gut dysbiosis, or a combination of all three. Obesity-prone (OP) and -resistant (OR) phenotypes are frequently observed in rodents, even in those given a high-fat diet (HFD). However, the underlying mechanisms are largely unknown. Male C57BL/6J mice were fed with chow or a HFD for 8 weeks. OP and OR mice were defined based on body weight gain, and integrated serum metabolic and gut microbial profiling was performed by the gas chromatography-mass spectroscopy-based metabolomic sequencing and pyrosequencing of 16S rDNA of cecum contents. A total of 60 differential metabolites were identified in comparisons among Con, OP, and OR groups, in which 27 were OP-related. These differential metabolites are mainly involved in glycolysis, lipids, and amino acids metabolism and the TCA cycle. Meanwhile, OP mice had a distinct profile in gut microbiota compared to those of OR or Con mice, which showed a reduced ratio of Firmicutes to Bacteroidetes and increased Proteobacteria. Moreover, the gut microbial alteration of OP mice was correlated with the changes of the key serum metabolites. OP-enriched Parasutterella from the Proteobacteria phylum correlated to most of metabolites, suggesting that it was essential in obesity. OP mice are distinct in metabolic and gut microbial profiles, and OP-related metabolites and bacteria are of significance for understanding obesity development.

The study was designed to investigate the possible mechanisms of hepatic microRNAs (miRs) in regulating local thyroid hormone (TH) action and ultimately different propensities to high-fat diet (HFD)-induced obesity. When obesity-prone (OP) and obesity-resistant (OR) mice were fed HFD for 7 weeks, OP mice showed apparent hepatic steatosis, with significantly higher body weight and lower hepatic TH receptor b (TRb) expression and type 1 deiodinase (DIO1) activity than OR mice. Next-generation sequencing technology revealed that 13 miRs in liver were dysregulated between the two phenotypes, of which 8 miRs were predicted to target on Dio1 or TRb When mice were fed for 17 weeks, OR mice had mild hepatic steatosis and increased Dio1 and TRb expression than OP mice, with downregulation of T3 target genes (including Srebp1c , Acc1 , Scd1 and Fasn ) and upregulation of Cpt1α , Atp5c1 , Cox7c and Cyp7a1 A stem-loop qRT-PCR analysis confirmed that the levels of miR-383, miR-34a and miR-146b were inversely correlated with those of DIO1 or TRb. Down-regulated expression of miR-383 or miR-146b by miR-383 inhibitor (anti-miR-383) or miR-146b inhibitor (anti-miR-146b) in free fatty acid-treated primary mouse hepatocytes led to increased DIO1 and TRb expressions, respectively, and subsequently decreased cellular lipid accumulation, while miR-34a inhibitor (anti-miR-34a) transfection had on effects on TRb expression. Luciferase reporter assay illustrated that miR-146b could directly target TRb 3'untranslated region (3'UTR). These findings suggested that miR-383 and miR-146b might play critical roles in different propensities to diet-induced obesity via targeting on Dio1 and TRb , respectively., (© 2017 Society for Endocrinology.)

Scope: Activation of endothelial adenosine monophosphate-activated protein kinase (AMPK) contributes to increase nitric oxide (NO) availability. The aim of this study was to assess if high-fat diet (HFD)-induced endothelial dysfunction is linked to AMPK deregulation., Methods and Results: Twelve-week-old Sprague Dawley male rats were assigned either to control (10 kcal % from fat) or to HFD (45 kcal % from fat) for 8 wk. HFD rats segregated in obesity-prone (OP) or obesity-resistant (OR) rats according to body weight. HFD triggered an impaired glucose management together with impaired endothelium-dependent relaxation, reduced endothelial AMPK activity and lower NO availability in aortic rings of OP and OR cohorts. Relaxation evoked by AMPK activator, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) was reduced in both OP and OR rings, which exhibited lower p-AMPKα-Thr(172) /AMPKα ratios that negatively correlated with plasma non-esterified fatty acids (NEFA) and triglycerides (TG). Inhibition of PI3K (wortmannin, 10(-7) M) or Akt (triciribine, 10(-5) M) reduced relaxation to AICAR only in the control group (p < 0.001). Akt (p-Akt-Ser(473) ) and eNOS phosphorylation (p-eNOS-Ser(1177) ) were significantly reduced in OP and OR (p < 0.01)., Conclusion: Endothelial dysfunction caused by HFD is related to a dysfunctional endothelial AMPK-PI3K-Akt-eNOS pathway correlating with the increase of plasma NEFA, TG, and an impaired glucose management., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)