Food-seeking behavior is triggered by skin ultraviolet exposure in males.

Sexual dimorphisms are responsible for profound metabolic differences in health and behavior. Whether males and females react differently to environmental cues, such as solar ultraviolet (UV) exposure, is unknown. Here we show that solar exposure induces food-seeking behavior, food intake, and food-seeking behavior and food intake in men, but not in women, through epidemiological evidence of approximately 3,000 individuals throughout the year. In mice, UVB exposure leads to increased food-seeking behavior, food intake and weight gain, with a sexual dimorphism towards males. In both mice and human males, increased appetite is correlated with elevated levels of circulating ghrelin. Specifically, UVB irradiation leads to p53 transcriptional activation of ghrelin in skin adipocytes, while a conditional p53-knockout in mice abolishes UVB-induced ghrelin expression and food-seeking behavior. In females, estrogen interferes with the p53-chromatin interaction on the ghrelin promoter, thus blocking ghrelin and food-seeking behavior in response to UVB exposure. These results identify the skin as a major mediator of energy homeostasis and may lead to therapeutic opportunities for sex-based treatments of endocrine-related diseases.

Can hair steroids predict pregnancy longevity?

Maintaining pregnancy to term is important as preterm delivery is a risk factor for impaired infant development, which may have negative long-term consequences. Therefore, developing biomarkers that can predict pregnancy longevity during early gestation is essential for the prevention of preterm birth. Here we explored whether maternal hair testosterone and cortisol, representing the pre-conception and first trimester periods respectively, may be used to predict pregnancy longevity. We recruited 125 pregnant women that contributed hair samples and answered a personal information questionnaire that included pre-conception smoking. We quantified steroids using commercial enzyme-linked immunosorbent assay kits. Gestational age at delivery was obtained from medical records. We used General Linear Models to predict gestation length. The model that included first trimester cortisol, pre-conception smoking, pre-conception testosterone and the interaction between first trimester cortisol and pre-conception smoking predicted 13% of the variance in gestation length (R2 = 0.130; n = 105; p = 0.007). First trimester cortisol was the best predictor of gestational length. Women with high levels of cortisol in their first trimester had an increased probability of a full-term delivery. The effect of cortisol was especially pronounced in smokers (ß = 1.69), compared to non-smokers (ß = 0.45). Pre-conception testosterone also contributed to the model. Our study suggests that hair steroids may be used to predict pregnancy longevity, together with other contributing factors.

Overweight and CpG methylation of the Pomc promoter in offspring of high-fat-diet-fed dams are not "reprogrammed" by regular chow diet in rats.

This study aimed to determine whether epigenetic malprogramming induced by high-fat diet (HFD) has an obesogenic effect on nonmated and mated female rats and their offspring. Further, it aimed to reprogram offspring's epigenetic malprogramming and phenotype by providing normal diet after weaning. Body weight (BW) was measured, and plasma and hypothalamic arcuate nuclei were collected for analysis of hormones, mRNA, and DNA CpG methylation of the promoter of Pomc, a key factor in control of food intake. In nonmated females, HFD decreased Pomc/leptin ratio by ∼38%. This finding was associated with Pomc promoter hypermethylation. While heavier during pregnancy, during lactation HFD dams showed sharper BW decrease (2.5-fold) and loss of Pomc promoter hypermethylation. Moreover, their weight loss was correlated with demethylation (r=-0.707) and with gadd45b mRNA expression levels (r=0.905). Even though offspring of HFD dams ate standard chow from weaning, they displayed increased BW, Pomc promoter hypermethylation, and vulnerability to HFD challenge (3-fold kilocalorie intake increase). These findings demonstrate a long-term effect of maternal HFD on CpG methylation of the Pomc promoter in the offspring, which was not reprogrammed by standard chow from weaning. Further, the results suggest a possible mechanism of demethylation of the Pomc promoter following pregnancy and lactation.

Adolescent rats are more prone to binge eating behavior: a study of age and obesity as risk factors.

Binge eating (BE) is characterized by repeated, intermittent over-consumption of food in a brief period of time. This study aims to advance the understanding of potential risk factors for BE such as obesity, overeating and adolescence as an age group. We used the Otsuka Long Evans Tokushima Fatty (OLETF) rat, a genetic overeating-induced obesity model with increased preferences for sweet and fat. Adolescent and adult rats from both strains (OLETF and the lean control strain, Long Evans Tokushima Otsuka [LETO]) received limited access to a palatable liquid diet (Ensure vanilla) for three weeks. Water and chow were available throughout the study, but access to Ensure was limited to two hours, three times a week (3TW group) or every work day (5TW group). As expected, OLETF rats consumed more Ensure and were more BE-prone (BEP) than LETO rats at both ages. Adolescent rats showed a significantly larger binge size as demonstrated by a greater increase in Ensure intake, compared to adults. Furthermore, while the adults reduced their chow intake, compensating for increased Ensure intake, the adolescents increased their chow intake too. Finally, the adolescent rats showed binge like behavior earlier in the study and they tended to be BEP more than the adults. Our findings in rats suggest that adolescents and in particular obese adolescents are at risk for BE, and BE can lead to overweight, thus providing the basis for examination of biological mechanisms of this process in animal models.

Cholecystokinin modulation of maternal behavior

Maternal behavior is regulated by several neurotransmitters, neuropeptides, and hormones. This mini-review focuses on the role of cholecystokinin (CCK), a neuropeptide and gut hormone best known as a satiety signal, in mediating maternal behavior. In addition to the role of CCK in the infant in mother-infant interactions, maternal CCK appears to also be important. We discuss maternal behavior research, mainly in rats, that has examined the effect of administering CCK to dams, CCK-opioid interactions, and maternal behavior in rats that lack CCK1 receptors. We discuss the possibility that CCK might play a role in neurological adjustments during pregnancy that ultimately influence behavioral adaptations by the offspring during lactation. Finally, we hypothesize that maternal CCK is also involved in maternal memory and reward...

Selective leptin insensitivity and alterations in female-reproductive patterns linked to hyperleptinemia during infancy.

The dramatic increase in the prevalence of childhood obesity worldwide makes the investigation of its early developmental stages and effective prevention strategies an urgent issue. CCK1 deficient OLETF rats are a model of obesity previously used to study the early phases of this disorder. Here, we exposed wild type (LETO) females to an early obesogenic environment and genetically obese OLETF females to a lean postnatal environment, to assess long term alterations in leptin sensitivity, predisposition to diet induced obesity and adult female health. We found that genetically lean females reared by obese mothers presented early postnatal hyperleptemia, selectively reduced response to leptin and sensitivity to diet induced obesity when exposed to a high palatable diet as adults. The estrous cycle structure and intake profile were permanently disrupted, despite presenting normal adiposity/body weight/food intake. Genetically obese females reared by lean dams showed normalized early levels of leptin and reduced body weight, food intake and body fat at adulthood; normalized estrous cycle structure and food intake across the cycle, improved hormonal profile and peripheral leptin sensitivity and a remarkable progress in self-control when exposed to a high fat/palatable diet. Altogether, it appears that the early postnatal environment plays a critical role in determining later life coping with metabolic challenges and has an additive effect on the genetic predisposition that makes OLETF females morbidly obese as adults. This work also links, for the first time, alterations in the leptin system during early development to later life abnormalities related to female reproduction and health.

Feeding and reward: ontogenetic changes in an animal model of obesity.

Given that food is a natural reinforcement, deficits in the reward system can lead to disordered eating behavior, inducing or worsening an already existing pre-obese phenotype. In order to evaluate developmental, food-reward-related measures we used the OLETF rat, an animal model of early-onset overeating-induced obesity, and a natural CCK-1 receptor knockout. Dopamine-like-receptor type 1 (D1R) and D2R levels were examined in a reward-related brain area (Nac shell) and sucrose preference was assessed at selected time points from weaning to adulthood (postnatal day [PND]90). In addition, a group of OLETF was pair fed (PF) to the amount of food consumed by same-age LETO controls (from weaning to PND 90) to examine the contribution of overweight to the alteration in DR expression. In addition, we examined food "craving"-like behavior by analyzing microstructural patterns of licking a palatable liquid diet. OLETF rats expressed significantly lower D2R levels than LETO controls only on PND 90. In PF OLETF, weight and D2R levels were normalized. In addition, OLETF presented exaggerated preference for the high sucrose concentration. After 30-day abstinence, OLETF rats presented significant increased initial rate of licking, suggesting food "craving". Thus, adult OLETF rats demonstrated altered D2R signaling similar to drug-induced sensitization, suggesting a link with their avidity for sucrose and their abnormal craving response. However, the current findings of a late deficit appearance and the novel PF results suggest that deficits in the motivation/regulatory systems of the OLETF rat are a developing process (at least from weaning and on) depending on the overeating and obese phenotype of the rats and not only on the CCK mutation.

Maternal environmental contribution to adult sensitivity and resistance to obesity in Long Evans rats.

BACKGROUND: The OLETF rat is an animal model of early onset hyperphagia induced obesity, presenting multiple pre-obese characteristics during the suckling period. In the present study, we used a cross-fostering strategy to assess whether interactions with obese dams in the postnatal environment contributed to the development of obesity. METHODOLOGY: On postnatal Day (PND)-1 OLETF and control LETO pups were cross-fostered to same or opposite strain dams. An independent ingestion test was performed on PND11 and a nursing test on PND18. Rats were sacrificed at weaning or on PND90, and plasma leptin, insulin, cholesterol, triglycerides and alanine aminotransferase (ALT) were assayed. Fat pads were collected and weighed and adipocyte size and number were estimated. Body weight and intake, as well as the estrous cycle of the female offspring were monitored. PRINCIPAL FINDINGS: During the suckling period, the pups' phenotype was almost completely determined by the strain of the mother. However, pups independently ingested food according to their genotype, regardless of their actual phenotype. At adulthood, cross fostered males of both strains and LETO females were affected in regard of their adiposity levels in the direction of the foster dam. On the other hand, OLETF females showed almost no alterations in adiposity but were affected by the strain of the dams in parameters related to the metabolic syndrome. Thus, OLETF females showed reduced liver adiposity and circulating levels of ALT, while LETO females presented a disrupted estrous cycle and increased cholesterol and triglycerides in the long term. CONCLUSIONS: The present study provides further support for the early postnatal environment playing a sex-divergent role in programming later life phenotype. In addition, it plays a more central role in determining the functioning of mechanisms involved in energy balance that may provide protection from or sensitivity to later life obesity and pathologies related to the metabolic syndrome.

Post-weaning voluntary exercise exerts long-term moderation of adiposity in males but not in females in an animal model of early-onset obesity.

Given the alarming increase in childhood, adolescent and adult obesity there is an imperative need for understanding the early factors affecting obesity and for treatments that may help prevent or at least moderate it. Exercise is frequently considered as an effective treatment for obesity however the empirical literature includes many conflicting findings. In the present study, we used the OLETF rat model of early-onset hyperphagia-induced obesity to examine the influence of early exercise on peripheral adiposity-related parameters in both males and females. Rats were provided voluntary access to running wheels from postnatal day (PND) 22 until PND45. We examined fat pad weight (brown, retroperitoneal, inguinal and epididymal); inguinal adipocyte size and number; and leptin, adiponectin, corticosterone and creatinine levels. We also examined body weight, feeding efficiency and spontaneous intake. Early voluntary exercise reduced intake, adiposity and leptin in the OLETF males following a sharp reduction in adipocyte size despite a significant increase in fat cell number. Exercising males from the lean LETO control strain presented stable intake, but reduced body fat, feeding efficiency and increased plasma creatinine, suggesting an increment in muscle mass. OLETF females showed reduced feeding efficiency and liver fat, and a significant increase in brown fat. Exercising LETO control females increased intake, body weight and creatinine, but no changes in body fat. Overall, OLETF rats presented higher adiponectin levels than controls in both basal and post-exercise conditions. The results suggest an effective early time frame, when OLETF males can be successfully "re-programmed" through voluntary exercise; in OLETF females the effect is much more moderate. Findings expose sex-dependent peripheral mechanisms in coping with energy challenges.

Attenuation of obesity by early-life food restriction in genetically hyperphagic male OLETF rats: peripheral mechanisms.

The alarming increase in childhood, adolescent and adult obesity has exposed the need for understanding early factors affecting obesity and for treatments that may help prevent or moderate its development. In the present study, we used the OLETF rat model of early-onset hyperphagia induced obesity, which become obese as a result of the absence of CCK(1) receptors, to examine the influence of partial food restriction on peripheral adiposity-related parameters during and after chronic and early short-term food restriction. Pair feeding (to the amount of food eaten by control, LETO rats) took place from weaning until postnatal day (PND) 45 (early) or from weaning until PND90 (chronic). We examined fat pad weight (brown, retroperitoneal, inguinal and epididymal); inguinal adipocyte size and number; and plasma leptin, oxytocin and creatinine levels. We also examined body weight, feeding efficiency and spontaneous intake after release from food-restriction. The results showed that chronic food restriction produced significant reductions in adiposity parameters, hormones and body weight, while early food restriction successfully reduced long-term body weight, intake and adiposity, without affecting plasma measurements. Early (and chronic) dieting produced promising long-term effects that may imply the reorganization of both peripheral and central mechanisms that determine energy balance and further support the theory suggesting that early interventions may effectively moderate obesity, even in the presence of a genetic tendency.

Microstructural pattern of palatable food intake from weaning to adulthood in male and female OLETF rats.

Ontogenetic trajectories from weaning to adulthood and sex differences in feeding patterns were examined in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model of early onset overeating-induced obesity, and a natural cholecystokinin-1 receptor knockout. Overnight patterns of licking a palatable liquid diet (Ensure) were analyzed on Postnatal Days 22, 38, 60, and 90. Because different microstructure profiles may reflect alterations in the influence of positive and negative signals, we examined meal parameters to uncover developing mechanisms underlying eating behavior in this strain. OLETF rats displayed significantly greater caloric intake, larger meals (in number of licks), and more (within-meal) clusters of feeding (which were shorter in duration and contained fewer licks per cluster) than did Long-Evans Tokushima Ohtsuka (LETO) strain controls. OLETF rats also had significantly lower satiety ratios than LETO rats. Moreover, we identified sex differences in the age of emergence of microstructural patterns of obesity-related overeating, suggesting that systems other than cholecystokinin may be disrupted, possibly worsening the OLETF strain's obesity phenotype.

Development of obesity in the Otsuka Long-Evans Tokushima Fatty rat.

Understanding the early factors affecting obesity development in males and females may help to prevent obesity and may lead to the discovery of more effective treatments for those already obese. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat model of obesity is characterized by hyperphagia-induced obesity, due to a spontaneous lack of CCK(1) receptors. In the present study, we focused on the behavioral and physiological aspects of obesity development from weaning to adulthood. We examined body weight, feeding efficiency, fat pad [brown, retroperitoneal, inguinal and epydidimal (in males)] weight, inguinal adipocyte size and number, leptin and oxytocin levels, body mass index, waist circumference, and females' estrous cycle structure. In the males, central hypothalamic gene expression was also examined. OLETF rats presented overall higher fat and leptin levels, larger adipocytes, and increased waist circumference and BMI from weaning until adulthood, compared with controls. Analysis of developmental patterns of gene expression for hypothalamic neuropeptides revealed peptide-specific patterns that may underlie or be a consequence of the obesity development. Analysis of the developmental trajectories toward obesity within the OLETF strain revealed that OLETF females developed obesity in a more gradual manner than the males, presenting delayed obesity-related "turning points," with reduced adipocyte size but larger postweaning fat pads and increased adipocyte hyperplasia compared with the males. Intake decrease in estrus vs. proestrus was significantly less in OLETF vs. Long-Evans Tokushima Otsuka females. The findings highlight the importance of using different sex-appropriate approaches to increase the efficacy of therapeutic interventions in the treatment and prevention of chronic early-onset obesity.

The endocannabinoid system during development: emphasis on perinatal events and delayed effects.

The endocannabinoid system (ECS) including its receptors, endogenous ligands ("endocannabinoids"), synthesizing and degradating enzymes, and transporter molecules has been detected from the earliest embryonal stages and throughout pre- and postnatal development; endocannabinoids, notably 2-arachidonoylglycerol, are also present in maternal milk. During three developmental stages, (1) early embryonal, (2) prenatal brain development, and (3) postnatal suckling, the ECS plays an essential role for development and survival. During early gestation, successful embryonal passage through the oviduct and implantation into the uterus require critical enzymatic control of the endocannabinoids. During fetal life, endocannabinoids and the cannabinoid CB(1) receptor are important for brain development, regulating neural progenitor differentiation and guiding axonal migration and synaptogenesis. Postnatally, CB(1) receptor activation by 2-arachidonoylglycerol appears to play a critical role in the initiation of milk suckling in mouse pups, possibly by enabling innervation and/or activation of the tongue muscles. Perinatal manipulation of the ECS, by administering cannabinoids or by maternal marijuana consumption, alters neurotransmitter and behavioral functions in the offspring. Interestingly, the sequelae of prenatal cannabinoids are similar to many effects of prenatal stress, which may suggest that prenatal stress impacts on the ECS and that vice versa prenatal cannabinoid exposure may interfere with the ability of the fetus to cope with the stress. Future studies should further clarify the mechanisms involved in the developmental roles of the ECS and understand better the adverse effects of prenatal exposure, to design strategies for the treatment of conditions including infertility, addiction, and failure-to-thrive.

Toward an animal model of childhood-onset obesity: follow-up of OLETF rats during pregnancy and lactation.

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat model of obesity (a spontaneous CCK1 receptor knockout) has been extensively studied as model of hyperphagia-induced obesity. In previous studies, young OLETF rats presented abnormal eating patterns [compared with Long-Evans Tokushima Otsuka (LETO) controls] in a variety of independent ingestion and nursing tests during the suckling period. The aim of the present study was to characterize the early emergence of abnormal adiposity in the pups. Moreover, because both the dams and the pups present the genetic mutation, a close follow-up of the dams' body weight and intake during pregnancy and lactation was performed to examine the circumstances that contribute to build up the pups' early adiposity. Compared with controls, OLETF pups presented higher fat levels, larger adipocytes, and increased waist circumference as early as postnatal day 7 and this profile persisted to the age of weaning. While LETO dams gained weight throughout pregnancy and lactation, OLETF dams were obese and hyperphagic during pregnancy but lost weight during lactation, probably as a result of rearing hyperphagic pups. Current and previous results suggest a possible influence of the dams' obesity during gestation and a high investment in nursing time during lactation on the pups' obesity levels during childhood. This, combined with the innate hyperphagia repeatedly observed in the pups at these early ages, makes the OLETF strain a useful tool in the research of childhood-onset obesity.

Diurnal and nocturnal nursing behavior in the OLETF rat.

The Otsuka Long Evans Tokushima Fatty (OLETF) rat model of obesity has been recently found to develop hyperphagia and obesity early in life. Our goal was to investigate the dams' nursing behavior during the day and the night in order to elucidate their contribution to the pre-obesity of the pups. We examined nursing bout number, length, posture, initiative, nursing total time and frequency of other maternal behaviors over the three postpartum (PP) weeks. In the first week, OLETF dams nursed more during the day and presented more self-directed activities during the night. In the third PP week, OLETF dams displayed increased nursing time, bout number, nursing frequency, and supine postures at the beginning of the nursing episodes and less active self-directed behaviors, both day and night, while OLETF pups displayed more initiative in starting nursing bouts. The results suggest a circadian difference in nursing behavior and self-directed activities between the strains on PP week 1 and a strong influence of the OLETF pups on the nursing behavior of the dam on PP week 3, which contributes to their obese features.

Gastric preloads of corn oil and mineral oil produce different patterns of increases of c-Fos-like immunoreacitve cells in the brain of 9-12 day-old rats.

Equivolumetric gastric preloads of corn oil and mineral oil administered to rats on postnatal day 12 (P12) inhibited intake equally during a 30-min test of independent ingestion (II), but preloads of corn oil inhibited intake significantly more than preloads of mineral oil on P15 and P18 [Weller, A., Gispan, I.H., Armony-Sivan, R., Ritter, R.C., Smith, G.P., 1997. Preloads of corn oil inhibit independent ingestion on postnatal day 15 in rats. Physiol. Behav. 62, 871-874]. It is possible that the equivalent inhibition of intake by the oil preloads on P12 resulted from the failure of the preabsorptive sensory properties of the preloads to be discriminated by peripheral or central sensory mechanisms. To investigate this possibility, we administered equivolumetric gastric preloads of 25% corn oil and 25% mineral oil to pups on P9-12 and counted the number of c-Fos-like immunoreactive (CFLI) cells in central sites that are activated by food intake and postingestive preabsortive mechanisms in adult rats and in pups on P10-11. The major result was that preloads of 25% corn oil and 25% mineral oil that produced equivalent inhibition of II intake produced differential increases of CFLI cells in the forebrain and hindbrain. Specifically, preloads of corn oil increased the number of CFLI cells in the caudal Nucleus Tractus Solitarius significantly more than preloads of mineral oil. Furthermore, preloads of corn oil increased the number of CFLI cells in the Paraventricular and Supraoptic nuclei, but preloads of mineral oil did not. This differential pattern of increases of CFLI cells is evidence that the brain discriminates the preabsorptive sensory properties of preloads of corn oil and mineral oil on P9-12.

The ontogeny of postingestive inhibitory stimuli: examining the role of CCK.

Cholecystokinin (CCK) inhibits food intake in adults. This paper describes research examining the ability of CCK to affect feeding in infant rats and the role of CCK in the developmentally emerging ability of the rat pup to inhibit ingestion in response to sensory characteristics of food. First, data will be described from studies that asked if the CCK system is functional in preweanling rats. Specifically, these studies examined whether exogenous and endogenous CCK can decrease intake of the infant rat during independent ingestion (of a milk diet, away from the dam). In addition, the ability of exogenous CCK to activate central feeding-control areas in the brain stem and hypothalamus in infant rats was examined by C-FOS staining. Next, experiments examining which specific intake-inhibitory sensory aspects of food are mediated by CCK will be described. The volume, hypertonicity, fat, carbohydrate and protein content of a preload were separately manipulated in different studies, followed closely by a 30-min test meal. The selective CCK(1) receptor antagonist devazepide was used to assess CCK mediation of the control of intake produced by particular sensory aspects of food, at the earliest age in which this ability to control intake appears. Finally, the pattern of independent ingestion in infant OLETF rats lacking CCK(1) receptors was examined. The results suggest that the CCK intake-inhibitory mechanism is potentially available to the young, suckling pup even before it starts to feed on its own. However, it appears to mediate only a portion of the controls of intake during nursing and early stages of weaning. Some aspects of the CCK system (e.g., forebrain-hindbrain connections) and CCK's role in mediating the effects of other stimulus aspects of food apparently undergo a post-weaning maturational process.