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The current prevalence of obesity has been linked to the consumption of highly palatable foods and may be mediated by a dysregulated or hyposensitive orosensory perception of dietary fat, thereby contributing to the susceptibility to develop obesity. The goal of the current study was to investigate the role of lingual taste input in obesity-prone (OP, Osborne-Mendel) and obesity-resistant (OR, S5B/Pl) rats on the consumption of a high-fat diet (HFD). Density of fungiform papillae was assessed as a marker of general orosensory input. To determine if orosensory afferent input mediates dietary fat intake, surgical transection of the chorda tympani and glossopharyngeal nerves (GLX/CTX) was performed in OP and OR rats and HFD caloric intake and body weight were measured. Fungiform papillae density was lower in OP rats, compared with OR rats. GLX/CTX decreased orosensory input in both OP and OR rats, as measured by an increase in the intake of a bitter, quinine solution. Consumption of low-fat diet was not altered by GLX/CTX in OP and OR rats; however, GLX/CTX decreased HFD intake in OR, without altering HFD intake in OP rats. Overall, these data suggest that inhibition of orosensory input in OP rats do not decrease fat intake, thereby supporting that idea that hyposensitive and/or dysregulated orosensory perception of highly palatable foods contribute to the susceptibility to develop obesity.

OBJECTIVE The current study aimed to identify how sex influences neurobiological responses to food cues, particularly those related to hedonic eating, and how this relates to obesity propensity, using functional magnetic resonance imaging (fMRI). METHODS Adult men and women who were either obesity resistant (OR) or obesity prone (OP) underwent fMRI while viewing visual food cues (hedonic foods, neutral foods, and nonfood objects) in both fasted and fed states. RESULTS When fasted, a significant sex effect on the response to hedonic vs. neutral foods was observed, with greater responses in women than men in the nucleus accumbens (P = 0.0002) and insula (P = 0.010). Sex-based differences were not observed in the fed state. No significant group effects (OP vs. OR) or group-by-sex interactions were observed in fasted or fed states. CONCLUSIONS Greater fasted responses to hedonic food cues in reward-related brain regions were observed in women compared with men, suggesting that women may be more sensitive to the reward value of hedonic foods than men when fasted. This may indicate sex-dependent neurophysiology underlying eating behaviors.

Heart failure with preserved ejection fraction (HFpEF) is a common and complex syndrome with high mortality and morbidity rates for which there are currently no evidence-based therapies. As patients with HFpEF very often harbor comorbidities of metabolic syndrome, we hypothesized, that metabolic syndrome in aging animals could be a major mechanism underlying the development of diastolic dysfunction and HFpEF. Therfeore, obesity-prone (OP) and -resistant (OR) rats were respectively fed with a high-fat diet (HFD) or a standard rat chow (Std) for 4 months or for 12 months (n = 10 rats in each group; 4 groups). At the end of the protocol, abdominal obesity, complete phenotyping of metabolic syndrome, associated to echocardiographic and left and right ventricular catheterization measurements, were performed. Blood was sampled before euthanasia of the animals. After 4- and 12-month HFD, OP rats presented increased total body and abdominal fat weights, altered glucose tolerance test and dyslipidemia. In OP rats, left ventricular systolic (164 ± 6 versus 120 ± 5 mmHg, P Metabolic syndrome induced by 12-month HFD in OP rats leads to the development of HFpEF. In these rats, circulating NT-proBNP levels were decreased, while circulating ST2 levels were largely increased.

Obesity results from overconsumption of energy, partly because of the inability to refrain from highly palatable rewarding foods. Even though palatable food is available to everyone, only a fraction of the population develops obesity. We previously showed that following chronic exposure to highly palatable food animals that gained the most weight also showed addictive-like motivation to seek for palatable food. An important question remains-is this extreme, addictive-like, motivation to consume palatable food the cause or the consequence of diet-induced obesity? Here, we show that obesity-prone (OP) mice exhibit higher motivation for palatable food consumption compared with obesity-resistant mice even before developing obesity, but that the full manifestation of this high motivation to eat is expressed only after chronic exposure to high-fat-high-sugar (HFHS) diet. HFHS diet also impairs performance in the operant food-seeking task selectively in OP mice, an impairment that persists even after 2 weeks of abstinence from HFHS food. Overall, our data suggest that while some aspects of food motivation are high in OP mice already before developing obesity, the chronic exposure to HFHS food accentuates it and drives the development of obesity.

Background/Objectives Expanding visceral adiposity is associated with increased inflammation and increased risk for developing obesity-related comorbidities. The goal of this study was to examine high fat diet (HFD)-induced differences in adipocyte size and cytokine/chemokine expression in visceral and subcutaneous adipose depots in obesity-prone (OP) and obesity-resistant (OR) rats. Methods OP and OR rats were fed either a low fat diet (LFD, 10% kilocalories from fat) or HFD (60% kilocalories from fat) for 7 weeks. Adipocyte size and the presence of crown-like structures in epididymal and inguinal adipose tissue were determined. A multiplex cytokine/chemokine panel was used to assess the expression of inflammatory markers in epididymal and inguinal adipose tissues. Results A higher percentage of large adipocytes (> 5000 μm2) was detected in the epididymal and inguinal adipose tissues of OP rats and a higher percentage of small adipocytes (< 4000 μm2) was detected in the epididymal and inguinal adipose tissues of OR rats. More crown-like structures were identified in epididymal adipose tissue of OP rats fed a LFD, compared to OR rats. Consumption of a HFD increased the number of crown-like structures in OR, but not OP rats. Epididymal expression of pro-inflammatory cytokines (IL-1β, TNF-α) was higher in OP rats, compared to OR rats fed LFD. HFD consumption increased epididymal expression of GM-CSF, IL-1α, IL-1β, IL-6, MIP-2, and TNF-α in OP and OR rats. Inguinal expression of pro-inflammatory cytokines (IL-1α, IL-1β, TNF-α) was higher in OP rats, compared to OR rats. Conclusions Overall, these data suggest that a higher susceptibility to developing obesity is characterized by large adipocytes and increased visceral adipose inflammation. Interestingly, in OR rats, the detrimental effects of HFD consumption on visceral adipose inflammation are evident with only small increases in weight and adiposity, suggesting that HFD also increases the risk for obesity-related comorbidities in OR rats.

Introduction Infants who are breastfed are introduced to a variety of flavors from the maternal milk and thus the transition from maternal milk to complementary foods seems easier for these children. Our aim was to investigate if duration of exclusive breastfeeding was associated with pickiness or dietary intake of vegetables, fruit, starch or sugar sweetened beverages in obesity prone normal weight children aged 2–6 years. Methods This cohort study was based on data from the Healthy Start primary intervention study, the Danish Medical Birth registry and the Danish Health Visitor's Child Health Database. Infant feeding was registered by health nurses while visiting the mother and child up to four times within the first year. Information on eating behaviour at age 2–6 years and the child's dietary intake were obtained by parents. Crude and adjusted logistic regression and general linear models were used to investigate associations. Results A total of 236 children had complete information on all variables. Data showed a tendency towards a higher risk of developing picky eating behaviour when breastfeed for Conclusions This study documents evidence that exclusive breastfeeding duration may influence pickiness and potentially facilitate the consumption of a healthier diet in later childhood in obesity prone normal weight children, which also have been reported in studies of children in general.

Objective Obesity is a costly, deadly public health problem for which new treatments are needed. Individual differences in meal pattern have been proposed to play a role in obesity risk. The present study tested the hypothesis that i) the microstructure of chronic high-fat diet intake differs between genetically selected Diet-Induced Obesity (DIO) and Diet Resistant (DR) rats, and ii) central administration of urocortin 2 (Ucn 2), a corticotropin-releasing factor type 2 (CRF2) agonist, decreases high-fat diet intake not only in lean DR rats, but also in obese DIO rats. Design Male, selectively bred DIO and DR rats (n=10/genotype) were chronically fed a high-fat diet. Food and water intake as well as ingestion microstructure were then compared under baseline conditions and following third intracerebroventricular injection of Ucn 2 (0, 0.1, 0.3, 1, 3 µg). Results Irrespective of genotype, Ucn 2 reduced nocturnal food intake with a minimum effective dose of 0.3 µg, suppressing high-fat diet intake by ~40% at the 3 µg dose. Ucn 2 also made rats of both genotypes eat smaller and briefer meals, including at doses that did not reduce drinking. Obese DIO rats ate fewer but larger meals than DR rats, which they ate more quickly and consumed with 2/3rd less water. Conclusions Unlike leptin and insulin, Ucn 2 retains its full central anorectic efficacy to reduce high-fat diet intake even in obese, genetically-prone DIO rats, which otherwise show a “gorging” meal pattern. These results open new opportunities of investigation towards treating some forms of diet-induced obesity.

Objective The roles that energy expenditure (EE) and nutrient oxidation play in a predisposition for weight gain in humans remains unclear. Subjects We measured EE and respiratory exchange ratio (RER) in non-obese obesity prone (OP; n=22) and obesity resistant (OR; n=30) men and women following a eucaloric diet and after 3 days of overfeeding (1.4x basal energy). Results Twenty four hour EE, adjusted for fat free mass and sex, measured while consuming a eucaloric diet was not different between OP and OR subjects (2367 ± 80 vs. 2285 ± 98 kcals; p=0.53). Following overfeeding, EE increased in both OP and OR (OP: 2506 ± 63.7, p0.05). Nighttime RER (~10pm-6:30am) did not change with overfeeding in OR (0.823 ± 0.02 vs. 0.837 ± 0.01, p=0.29), but increased significantly in OP subjects (0.798 ± 0.15 to 0.839 ± 0.15, p

Obesity and tobacco smoking represent the largest challenges to public health, but the causal relationship between nicotine and obesity is poorly understood. Nicotine suppresses body weight gain, a factor impacting smoking initiation and the failure to quit, particularly among obese smokers. The impact of nicotine on body weight regulation in obesity-prone and obesity-resistant populations consuming densely caloric diets is unknown. In the current experiment, body weight gain of adult male rats maintained on a high energy diet (31.8% kcal from fat) distributed into obesity-prone (OP), obesity-resistant (OR) and an intermediate group, which was placed on standard rodent chow (Chow). These rats were surgically implanted with intravenous catheters and allowed to self-administer nicotine (0 or 60 μg/kg/infusion, a standard self-administration dose) in 1-h sessions for 20 consecutive days. Self-administered nicotine significantly suppressed body weight gain but not food intake in OP and Chow rats. Self-administered nicotine had no effect on body weight gain in OR rats. These data suggest that: 1) OR rats are also resistant to nicotine-induced suppression of body weight gain; and 2) nicotine may reduce levels of obesity in a subset of smokers prone to obesity.

Obesity is a worldwide epidemic, and the comorbidities associated with obesity are numerous. Over the last two decades, we and others have employed an outbred rat model to study the development and persistence of obesity, as well as the metabolic complications that accompany excess weight. In this review, we summarize the strengths and limitations of this model and how it has been applied to further our understanding of human physiology in the context of weight loss and weight regain. We also discuss how the approach has been adapted over time for studies in females and female-specific physiological conditions, such as menopause and breast cancer. As excess weight and the accompanying metabolic complications have become common place in our society, we expect that this model will continue to provide a valuable translational tool to establish physiologically relevant connections to the basic science studies of obesity and body weight regulation.

Despite living in an environment that promotes weight gain in many individuals, some individuals maintain a thin phenotype while self-reporting expending little or no effort to control their weight. When compared with obesity prone (OP) individuals, we wondered if obesity resistant (OR) individuals would have higher levels of spontaneous physical activity (SPA) or respond to short-term overfeeding by increasing their level of SPA in a manner that could potentially limit future weight gain. SPA was measured in 55 subjects (23 OP and 32 OR) using a novel physical activity monitoring system (PAMS) that measured body position and movement while subjects were awake for 6 days, either in a controlled eucaloric condition or during 3 days of overfeeding (1.4× basal energy) and for the subsequent 3 days (ad libitum recovery period). Pedometers were also used before and during use of the PAMS to provide an independent measure of SPA. SPA was quantified by the PAMS as fraction of recording time spent lying, sitting, or in an upright posture. Accelerometry, measured while subjects were in an upright posture, was used to categorize time spent in different levels of movement (standing, walking slowly, quickly, etc.). There were no differences in SPA between groups when examined across all study periods (P > 0.05). However, 3 days following overfeeding, OP subjects significantly decreased the amount of time they spent walking (−2.0% of time, P = 0.03), whereas OR subjects maintained their walking (+0.2%, P > 0.05). The principle findings of this study are that increased levels of SPA either during eucaloric feeding or following short term overfeeding likely do not significantly contribute to obesity resistance although a decrease in SPA following overfeeding may contribute to future weight gain in individuals prone to obesity.

Background Osborne-Mendel (OM) rats are prone to obesity when fed a high fat diet, while 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 2h high fat meal following a 24h 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.

Gene-environment interactions play a role in the development of obesity but specific effects of diet on the orosensory detection of fatty acids have yet to be clarified. The objective of this study is to characterize the effect of prolonged (5-week) exposure to a high-fat (60%) diet on the behavioral sensitivity to the fatty acid linoleate following a conditioned taste aversion in obesity-prone and obesity-resistant rats. Exposure to the high-fat diet significantly enhanced the sensitivity of obesity-resistant (S5B/Pl) rats to linoleate while producing no effect on the fatty acid sensitivity for obesity-prone rats. Specifically, high-fat diet fed S5B/Pl rats showed stronger initial avoidance of linoleate and slower extinction rates than their normal diet cohorts. Our study suggests that prolonged dietary fat consumption may alter the behavioral sensitivity to fatty acids particularly in obesity-resistant animals.

Obesity is associated with increased risk of postmenopausal breast cancer resulting in recommendations for weight gain prevention and/or weight loss. However, there is little experimental data indicating if calorie restriction (CR) initiated in adulthood impacts mammary tumorigenesis. We have used female MMTV-TGF-α mice which develop mammary tumors in the 2nd yr of life as a model of postmenopausal breast cancer. From 10-30 weeks of age (woa) mice were fed a diet with 33% fat calories. At 30 woa based on body weight mice were classified as Obesity-Prone (Ob-Pr), Overweight (Ow) or Obesity-Resistant (Ob-R). Half in each weight category were then fed a 25% CR diet with reduced carbohydrate content (43% fat calories). The remaining mice continued on ad libitum (AL) feeding of the 33% fat diet. This resulted in six experimental groups (n = 26-31/group). Food intakes were monitored and body weights and mammary tumor status were determined weekly. Mice were sacrificed either at 90 woa or earlier if tumor size dictated. Mice in the CR-Ob-Pr group lost an average of 1.12 grams while mice in the AL-Ob-Pr group gained 16.03 grams from 30 woa until euthanasia. CR-Ob-Pr mice had a reduced palpable tumor incidence as compared to AL-Ob-Pr mice prior to euthanasia (12.90% versus 61.54% P = 0.0002). Indolent tumors were discovered at euthanasia with the CR-Ob-Pr mice having a larger number than AL-Ob-Pr mice resulting in final tumor positive mice in these groups of 54.84% vs 65.38%, respectively. Interestingly, the Ob-R mice had final tumor incidence of 38.71% and 73.08% for the CR-Ob-R vs the AL-Ob-R (P Citation Format: Michael E. Grossmann, Nancy K. Mizuno, Da-Qing Yang, D. Joshua Liao, Margot P. Cleary. Adult calorie restriction reduces weight gain and mammary tumor incidence in obesity prone MMTV-TFG α mice - [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1248. doi:10.1158/1538-7445.AM2017-1248

Background:Most children have periods in their life where they reject familiar as well as non-familiar food items and this is often referred to as pickiness. The consequences of pickiness may be malnutrition and, if prolonged, potentially lower body weight. However, studies investigating the consequence of pickiness on subsequent changes in diet intake and weight are limited.Objectives:To examine whether pickiness influences body mass index as well as diet intake over subsequent 15 months among obesity prone normal weight children aged 2–6 years.Methods:Data was obtained from the “Healthy Start” intervention study which included 271 children aged 2–6 years susceptible to overweight later in life. Information on pickiness was obtained from a parental questionnaire. Dietary habits were collected by 4-day dietary records filled in by the parents and height and weight were measured by trained health professionals and both measured twice over a 15 month period. Linear regression models were performed to assess the influence of pickiness on body mass index and diet with adjustments for possible confounders.Results:No differences in mean BMI Z-score were seen between picky/non-picky (P = 0.68) and little picky/non-picky (P = 0.68) children at 15 month follow-up. Picky children had a lower intake of protein (P = 0.01) than non-picky children despite no differences in total energy intake (P = 0.74), or in the other macronutrients, or the intake of fruit and vegetables, though children being a little picky had a lower intake of starch compared to non-picky children (P = 0.05). Results were essentially similar before and after adjustment for key covariates.Conclusion:Our study showed that BMI Z-score after 15 months follow-up was similar for picky and non-picky children. Picky children seemed to develop a lower protein intake despite similar total energy intake and diet composition.

International audience; Individuals exhibit a great variation in their body weight (BW) gain response to a high fat diet. Identification of predictive factors would enable better directed intervention toward susceptible individuals to treat obesity, and uncover potential mechanisms for treatment targeting. We set out to identify predictive behavioral and metabolic factors in an outbred rat model. 12 rats were analyzed in metabolic cages for a period of 5 days during both high carbohydrate diet (HCD), and transition to a high fat diet (HFD). After a recovery period, rats were given a HFD for 6 days to identify those resistant or sensitive to it according to BW gain. Rats were dissected at the end of the study to analyze body composition. This showed that small differences in final BW hid large variations in adiposity, allowing separation of rats into a second classification (final adiposity). Since these rats had been fed a HCD during most of their life, under which most of the adiposity presumably evolved, we considered this carbohydrate-sensitivity or -resistance. Meal size and meal number were found to be good predictors of sensitivity to a HFD, intensity of motor activity and ingestion speed good predictors of sensitivity to a HCD. Rats that were sensitive to the HCD could be resistant to the HFD and vice versa. This points to four types of individuals (carbohydrate/fat resistant/sensitive) though our sample size inhibited deeper investigation of this. This contributes to the idea that to be "obesity prone" does not necessarily need a HFD, it can also happen under a HCD, and be a hidden adiposity change with stable BW.

Vulnerability for weight gain is an individual trait. Obese people undertake dieting, but permanent weight loss is difficult to attain due to repeated phases of relapse to excess consumption.In this study, male Wistar rats were trained to operantly self-administer pellets followed by free-choice access in the homecage to high-fat high-sugar (HFHS) diet consisting of 30% sucrose, lard, standard rodent chow and water. Animals were divided into obesity-prone (OP) and obesity-resistant (OR) groups based on relative weight gain compared to normally fed controls despite equal consumption of HFHS.After 4 weeks of HFHS access, OP and OR animals did not differ in motivation for food pellets in terms of progressive ratio break point, lever pressing or response rate. However, upon discontinuation of the HFHS diet, differences between the OP and OR groups were noted. OP animals increased their motivation (i.e. craving) during the second withdrawal week and reduced time spent in the centre of an open field (increased anxiety) compared to the OR animals. Both OP and OR animals consumed less of the standard rodent chow during the first week of withdrawal when compared to normally fed controls. But, while the OR animals quickly returned to control levels of food consumption, OP animals continued to consume less standard rodent chow.The results show for the first time that withdrawal from free-choice HFHS induces craving that is specific to the OP animals and suggests that OP individuals may have withdrawal symptoms that are similar to those induced by addictive drugs.

Leptin produced by adipocytes controls body weight by restraining food intake and enhancing energy expenditure at the hypothalamic level. The diet-induced increase in fat mass is associated with the presence of elevated circulating leptin levels, suggesting the development of resistance to its anorectic effect. Rats, like humans, show different susceptibility to diet-induced obesity. The aim of the present study was to compare the degree of leptin resistance in obesity-prone (OP) vs obesity-resistant (OR) rats on a moderate high-fat (HF) diet and to establish if the effects of leptin on hypothalamo–pituitary endocrine functions were preserved. Starting from 6 weeks after birth, male Sprague–Dawley rats were fed on either a commercial HF diet (fat content: 20% of total calorie intake) or a standard pellet chow (CONT diet, fat content: 3%). After 12 weeks of diet, rats fed on HF diet were significantly heavier than rats fed on CONT diet. Animals fed on HF diet were ranked according to body weight; the two tails of the distribution were called OP and OR rats respectively. A polyethylene cannula was implanted into the right ventricle of rats 1 week before central leptin administration. After 12 weeks of HF feeding, both OR and OP rats were resistant to central leptin administration (10 μg, i.c.v.) (24 h calorie intake as a percent of vehicle-treated rats: CONT rats, 62 [50; 78]; OR, 93 [66; 118]; OP, 90 [70; 120] as medians and 95% confidence intervals (CIs) of six rats for each group). Conversely, after 32 weeks of diet both OR and OP rats were partially responsive to 10 μg leptin i.c.v. as compared with CONT rats (24 h calorie intake as a percent of vehicle-treated rats: CONT rats, 60 [50; 67]; OR, 65 [50; 80]; OP, 80 [60; 98] as medians and 95% CIs of six rats for each group); the decrease of food intake following 200 μg leptin i.p. administration was similar in all the three groups (calorie intake as a percent of vehicle-treated rats: 86 [80; 92] as median and 95% CI). The long-term intake of HF diet caused hyperleptinemia, hyperinsulinemia and higher plasma glucose levels in OP rats as compared with CONT rats. Plasma thyroxine (T4) was lower in all the rats fed the HF diet as compared with CONT. i.c.v. administration of leptin after 32 weeks of diet restored normal insulin levels in OP rats. Moreover, leptin increased plasma T4 concentration and strongly enhanced GH mRNA expression in the pituitary of OP as well as OR rats (180±10% vs vehicle-treated rats). In conclusion, long-term intake of HF diet induced a partial central resistance to the anorectic effect of leptin in both lean and fat animals; the neuroendocrine effects of leptin on T4 and GH were preserved.

Orexin A administration into the rostral lateral hypothalamic area (rLHa) stimulates spontaneous physical activity, and is much more effective at producing this activity in obesity-resistant (OR) rats as compared to obesity-prone (OP) rats. However, orexin A also stimulates wakefulness. Thus, it is possible that orexin A effects on spontaneous physical activity (or other orexin-mediated effects) are secondary to enhanced wakefulness in orexin A stimulated rats. To test this, we measured wakefulness following orexin A administration in OP and OR rats. We hypothesized that orexin A would stimulate greater levels of wakefulness in OR rats (compared to OP). To test this, rats were prepared with cannuale aimed at the rLHa, and EEG and EMG probes to record sleep/wake states by radiotelemetry. EEG and EMG waveforms were recorded for 2 h following orexin A (500 pmol) or vehicle injection. Data were hand scored to determine time spent in sleep/wake states (active wake, quiet wake, slow wave sleep, and rapid eye movement (REM)). Orexin A significantly increased active wake (p 0.05 for all comparisons), indicating that differences in behavioral responses (e.g. feeding, physical activity) to orexin A in OP and OR rats are not due to differences in wakefulness.