The model of litter size reduction induces long-term disruption of the gut-brain axis: An explanation for the hyperphagia of Wistar rats of both sexes.

The gut microbiota affects the host's metabolic phenotype, impacting health and disease. The gut-brain axis unites the intestine with the centers of hunger and satiety, affecting the eating behavior. Deregulation of this axis can lead to obesity onset. Litter size reduction is a well-studied model for infant obesity because it causes overnutrition and programs for obesity. We hypothesize that animals raised in small litters (SL) have altered circuitry between the intestine and brain, causing hyperphagia. We investigated vagus nerve activity, the expression of c-Fos, brain-derived neurotrophic factor (BDNF), gastrointestinal (GI) hormone receptors, and content of bacterial phyla and short-chain fatty acids (SCFAs) in the feces of adult male and female Wistar rats overfed during lactation. On the 3rd day after birth, litter size was reduced to 3 pups/litter (SL males or SL females) until weaning. Controls had normal litter size (10 pups/litter: 5 males and 5 females). The rats were killed at 5 months of age. The male and female offspring were analyzed separately. The SL group of both sexes showed higher food consumption and body adiposity than the respective controls. SL animals presented dysbiosis (increased Firmicutes, decreased Bacteroidetes) and had increased vagus nerve activity. Only the SL males had decreased hypothalamic GLP-1 receptor expression, while only the SL females had lower acetate and propionate in the feces and higher CCK receptor expression in the hypothalamus. Thus, overfeeding during lactation differentially changes the gut-brain axis, contributing to hyperphagia of the offspring of both sexes.

Intestinal NAPE-PLD contributes to short-term regulation of food intake via gut-to-brain axis.

Our objective was to explore the physiological role of the intestinal endocannabinoids in the regulation of appetite upon short-term exposure to high-fat-diet (HFD) and understand the mechanisms responsible for aberrant gut-brain signaling leading to hyperphagia in mice lacking Napepld in the intestinal epithelial cells (IECs). We generated a murine model harboring an inducible NAPE-PLD deletion in IECs (NapepldΔIEC). After an overnight fast, we exposed wild-type (WT) and NapepldΔIEC mice to different forms of lipid challenge (HFD or gavage), and we compared the modification occurring in the hypothalamus, in the vagus nerve, and at endocrine level 30 and 60 min after the stimulation. NapepldΔIEC mice displayed lower hypothalamic levels of N-oleoylethanolamine (OEA) in response to HFD. Lower mRNA expression of anorexigenic Pomc occurred in the hypothalamus of NapepldΔIEC mice after lipid challenge. This early hypothalamic alteration was not the consequence of impaired vagal signaling in NapepldΔIEC mice. Following lipid administration, WT and NapepldΔIEC mice had similar portal levels of glucagon-like peptide-1 (GLP-1) and similar rates of GLP-1 inactivation. Administration of exendin-4, a full agonist of GLP-1 receptor (GLP-1R), prevented the hyperphagia of NapepldΔIEC mice upon HFD. We conclude that in response to lipid, NapepldΔIEC mice displayed reduced OEA in brain and intestine, suggesting an impairment of the gut-brain axis in this model. We speculated that decreased levels of OEA likely contributes to reduce GLP-1R activation, explaining the observed hyperphagia in this model. Altogether, we elucidated novel physiological mechanisms regarding the gut-brain axis by which intestinal NAPE-PLD regulates appetite rapidly after lipid exposure.

Early weaning leads to disruption of homeostatic and hedonic eating behaviors and modulates serotonin (5HT) and dopamine (DA) systems in male adult rats.

Early weaning is associated with disruption of eating behavior. However, little is known about the mechanisms behind it. 5HT and DA systems are key regulators of homeostatic and hedonic eating behaviors, respectively. Thus, this study aims to evaluate the effects of early weaning on feeding behavior and 5HT and DA systems. For this, rats were submitted to regular (PND30) or early weaning (PND15) and between PND250 and PND300 were evaluated food intake of standard diet in response to 4 h food deprivation, during the 24 h period and per phase of the circadian cycle, in addition to the palatable food intake. Additionally, body mass and mRNA expression of 5HT1B, 5HT2C, SERT, DRD1 and DRD2 were evaluated in the hypothalamus and brainstem. The results demonstrate that early weaning promoted an increase in standard food intake in response to a 4 h food deprivation in the 24 h period and in the dark phase of the circadian cycle, in addition to an increased palatable food intake. No differences in body mass between regular or early weaning were observed. In the hypothalamus, increased mRNA expression of SERT and DRD1 was observed, but decreased 5HT1B mRNA expression. In the brainstem, the expression of 5HT1B, SERT, 5HT2C, DRD1 and DRD2 was increased in early weaned rats. In a nutshell, the stress promoted by early weaning has programmed the animals to be hyperphagic and to increase their palatable food intake, which was associated with modulation of 5HT and DA systems.

Demographic characteristics and delayed neurological sequelae risk factors in carbon monoxide poisoning.

AIM: Carbon monoxide (CO) is a colorless, odorless gas and tasteless. CO poisoning (COP) is one of the most frequently encountered inhalation poisonings. The most common cause of morbidity in COP is delayed neurological sequelae (DNS). DNS is the occurrence of neuropsychiatric findings within 2-240 days after discharge of patients with COP and there are no definitive diagnostic criteria. The aim of our study is; to determine the risk factors and incidence of DNS. METHOD: Our study is a retrospective, observational study. Patients with the diagnosis of COP in the emergency department between 2015 and 2016 were included in the study. Patients age, gender, findings in the initial physical examination (PE) and neurological examination (NE), blood carboxyhemoglobin (COHb) level, relation between hyperbaric oxygen (HBO) treatment and DNS were assessed. RESULTS: Total of 72 patients were included in the study. Mean age was 33.43 ±â€¯20.89. It was determined that pathological findings in the initial NE are a significant predictive factor for DNS (Odds ratio 18.600, p:0.004). Significant relation between NE and HBO treatment was present (p:00.1). There was no statistically significant relationship between initial COHb level and receiving HBO treatment (p:0.9). Median COHb level of patients with DNS was 30 (min:10, max: 43), median COHb level of patients without DNS was 25 (min:10, max:44) and there was no statistically significant relationship between the two groups according to COHb levels (p:0.7). CONCLUSION: Pathological findings in the initial neurological examination had a predictive value for delayed neurological sequelae in patients with carbon monoxide poisoning.

Potato-Resistant Starch Supplementation Improves Microbiota Dysbiosis, Inflammation, and Gut-Brain Signaling in High Fat-Fed Rats.

(1) High-fat (HF) diet leads to gut microbiota dysbiosis which is associated with systemic inflammation. Bacterial-driven inflammation is sufficient to alter vagally mediated satiety and induce hyperphagia. Promoting bacterial fermentation improves gastrointestinal (GI) epithelial barrier function and reduces inflammation. Resistant starch escape digestion and can be fermented by bacteria in the distal gut. Therefore, we hypothesized that potato RS supplementation in HF-fed rats would lead to compositional changes in microbiota composition associated with improved inflammatory status and vagal signaling. (2) Male Wistar rats (n = 8/group) were fed a low-fat chow (LF, 13% fat), HF (45% fat), or an isocaloric HF supplemented with 12% potato RS (HFRS) diet. (3) The HFRS-fed rats consumed significantly less energy than HF animals throughout the experiment. Systemic inflammation and glucose homeostasis were improved in the HFRS compared to HF rats. Cholecystokinin-induced satiety was abolished in HF-fed rats and restored in HFRS rats. HF feeding led to a significant decrease in positive c fiber staining in the brainstem which was averted by RS supplementation. (4) The RS supplementation prevented dysbiosis and systemic inflammation. Additionally, microbiota manipulation via dietary potato RS prevented HF-diet-induced reorganization of vagal afferent fibers, loss in CCK-induced satiety, and hyperphagia.

Prader-Willi syndrome: A model for understanding the ghrelin system.

Subsequent to the discovery of ghrelin as the endogenous ligand of growth hormone secretagogue receptor 1a, this unique gut peptide has been found to exert numerous physiological effects, such as appetite stimulation and lipid accumulation via the central regulating mechanisms in the hypothalamus, stimulation of gastric motility, regulation of glucose metabolism and brown fat thermogenesis, and modulation of stress, anxiety, taste sensation, reward-seeking behaviour and the sleep/wake cycle. Prader-Willi syndrome (PWS) has been described as a unique pathological state characterised by severe obesity and high circulating levels of ghrelin. It was hypothesised that hyperghrelinaemia would explain at least a part of the feeding behaviour and body composition of PWS patients, who are characterised by hyperphagia, an obsession with food and food-seeking, and increased adiposity. Initially, the link between hyperghrelinaemia and growth hormone deficiency, which is observed in 90% of the children with PWS, was not fully understood. Over the years, however, the increasing knowledge on ghrelin, PWS features and the natural history of the disease has led to a more comprehensive description of the abnormal ghrelin system and its role in the pathophysiology of this rare and complex neurodevelopmental genetic disease. In the present study, we (a) present the current view of PWS; (b) explain its natural history, including recent data on the ghrelin system in PWS patients; and (c) discuss the therapeutic approach of modulating the ghrelin system in these patients and the first promising results.

Altered R-spondin 1/CART neurocircuit in the hypothalamus contributes to hyperphagia in diabetes.

Hyperphagia is common in diabetes and may worsen hyperglycemia and diabetic complications. The responsible mechanisms are not well understood. The hypothalamus is a key center for the control of appetite and energy homeostasis. The ventromedial nucleus (VMH) and arcuate nucleus (ARC) are two critical nuclei involved in these processes. We have reported that R-spondin 1 (Rspo1) and its receptor leucin-rich repeat and G protein-coupled receptor 4 (LGR4) in the VMH and ARC suppressed appetite, but the downstream neuronal pathways are unclear. Here we show that neurons containing cocaine and amphetamine-regulated transcript (CART) in ARC express both LGR4 and insulin receptor; intracerebroventricular injection of Rspo1 induced c-Fos expression in CART neurons of ARC; and silencing CART in ARC attenuated the anorexigenic actions of Rspo1. In diabetic and obese fa/fa rats, Rspo1 mRNA in VMH and CART mRNA in ARC were reduced; this was accompanied by increased food consumption. Insulin treatment restored Rspo1 and CART gene expressions and normalized eating behavior. Chronic intracerebroventricular injection of Rspo1 inhibited food intake and normalized diabetic hyperphagia; intracerebroventricular injection of Rspo1 or insulin increased CART mRNA in ARC. In the CART neuron cell line, Rspo1 and insulin potentiated each other on pERK and ß-catenin, and in rats, they acted synergistically to inhibit food intake. Silencing Rspo1 in VMH reduced CART expression in ARC and attenuated the inhibitory effect of insulin on food intake. In conclusion, our data indicated that CART works downstream of Rspo1 and Rspo1 mediated the action of insulin centrally. The altered Rspo1/CART neurocircuit in the hypothalamus contributes to hyperphagia in diabetes. NEW & NOTEWORTHY This study reports that cocaine and amphetamine-regulated transcript (CART) neurons in the arcuate nucleus (ARC) of hypothalamus acted downstream of R-spondin 1 (Rspo1) to inhibit food intake. The Rspo1 mRNA level in ventromedial nucleus (VMH) and CART mRNA level in ARC were reduced in type 1 diabetic rat and obese fa/fa rat. Rspo1 and insulin acted synergistically on phospho-ERK and ß-catenin signal pathways and in suppressing food intake. The current results proposed that altered Rspo1/CART neurocircuit in the hypothalamus contributes to hyperphagia in diabetes.

The Hypothalamic Inflammatory/Gliosis Response to Neonatal Overnutrition Is Sex and Age Dependent.

Astrocytes participate in both physiological and pathophysiological responses to metabolic and nutrient signals. Although most studies have focused on the astrocytic response to weight gain due to high-fat/high-carbohydrate intake, surplus intake of a balanced diet also induces excess weight gain. We have accessed the effects of neonatal overnutrition, which has both age- and sex-dependent effects on weight gain, on hypothalamic inflammation/gliosis. Although both male and female Wistar rats accumulate excessive fat mass as early as postnatal day (PND) 10 with neonatal overnutrition, no increase in hypothalamic cytokine levels, markers of astrocytes or microglia, or inflammatory signaling pathways were observed. At PND 50, no effect of neonatal overnutriton was found in either sex, whereas at PND 150, males again weighed significantly more than their controls, and this was coincident with an increase in markers of inflammation and astrogliosis in the hypothalamus. Circulating triglycerides and free fatty acids were also elevated in these males, but not in females or in either sex at PND 10. Thus, the effects of fatty acids and estrogens on astrocytes in vitro were analyzed. Our results indicate that changes in circulating fatty acid levels may be involved in the induction of hypothalamic inflammation/gliosis in excess weight gain, even on a normal diet, and that estrogens could participate in the protection of females from these processes. In conclusion, the interaction of developmental influences, dietary composition, age, and sex determines the central inflammatory response and the associated long-term outcomes of excess weight gain.

Gender-specific alteration of energy balance and circadian locomotor activity in the Crtc1 knockout mouse model of depression.

Obesity and depression are major public health concerns, and there is increasing evidence that they share etiological mechanisms. CREB-regulated transcription coactivator 1 (CRTC1) participates in neurobiological pathways involved in both mood and energy balance regulation. Crtc1 -/- mice rapidly develop a depressive-like and obese phenotype in early adulthood, and are therefore a relevant animal model to explore possible common mechanisms underlying mood disorders and obesity. Here, the obese phenotype of male and female Crtc1 -/- mice was further characterized by investigating CRTC1's role in the homeostatic and hedonic regulation of food intake, as well as its influence on daily locomotor activity. Crtc1 -/- mice showed a strong gender difference in the homeostatic regulation of energy balance. Mutant males were hyperphagic and rapidly developed obesity on normal chow diet, whereas Crtc1 -/- females exhibited mild late-onset obesity without hyperphagia. Overeating of mutant males was accompanied by alterations in the expression of several orexigenic and anorexigenic hypothalamic genes, thus confirming a key role of CRTC1 in the central regulation of food intake. No alteration in preference and conditioned response for saccharine was observed in Crtc1 -/- mice, suggesting that mutant males' hyperphagia was not due to an altered hedonic regulation of food intake. Intriguingly, mutant males exhibited a hyperphagic behavior only during the resting (diurnal) phase of the light cycle. This abnormal feeding behavior was associated with a higher diurnal locomotor activity indicating that the lack of CRTC1 may affect circadian rhythmicity. Collectively, these findings highlight the male-specific involvement of CRTC1 in the central control of energy balance and circadian locomotor activity.

Microglial Inflammatory Signaling Orchestrates the Hypothalamic Immune Response to Dietary Excess and Mediates Obesity Susceptibility.

Dietary excess triggers accumulation of pro-inflammatory microglia in the mediobasal hypothalamus (MBH), but the components of this microgliosis and its metabolic consequences remain uncertain. Here, we show that microglial inflammatory signaling determines the immunologic response of the MBH to dietary excess and regulates hypothalamic control of energy homeostasis in mice. Either pharmacologically depleting microglia or selectively restraining microglial NF-κB-dependent signaling sharply reduced microgliosis, an effect that includes prevention of MBH entry by bone-marrow-derived myeloid cells, and greatly limited diet-induced hyperphagia and weight gain. Conversely, forcing microglial activation through cell-specific deletion of the negative NF-κB regulator A20 induced spontaneous MBH microgliosis and cellular infiltration, reduced energy expenditure, and increased both food intake and weight gain even in absence of a dietary challenge. Thus, microglial inflammatory activation, stimulated by dietary excess, orchestrates a multicellular hypothalamic response that mediates obesity susceptibility, providing a mechanistic rationale for non-neuronal approaches to treat metabolic diseases.

Eat and Death: Chronic Over-Eating.

Obesity-related co-morbidities decrease life quality, reduce working ability and lead to early death. The total amount of dietary fat consumption may be the most potent food-related risk factor for weight gain. In this respect, dietary intake of high-caloric, high-fat diets due to chronic over-eating and sedentary lifestyle lead to increased storage of triglycerides not only in adipose tissue but also ectopically in other tissues . Increased plasma concentrations of non-esterified free fatty acids and lipid-overloaded hypertrophic adipocytes may cause insulin resistance in an inflammation-independent manner. Even in the absence of metabolic disorders, mismatch between fatty acid uptake and utilization leads to the accumulation of toxic lipid species resulting in organ dysfunction. Lipid-induced apoptosis, ceramide accumulation, reactive oxygen species overproduction, endoplasmic reticulum stress, and mitochondrial dysfunction may play role in the pathogenesis of lipotoxicity. The hypothalamus senses availability of circulating levels of glucose, lipids and amino acids, thereby modifies feeding according to the levels of those molecules. However, the hypothalamus is also similarly vulnerable to lipotoxicity as the other ectopic lipid accumulated tissues. Chronic overnutrition most likely provides repetitive and persistent signals that up-regulate inhibitor of nuclear factor kappa B kinase beta subunit/nuclear factor kappa B (IKKß/NF-κB) in the hypothalamus before the onset of obesity. However, the mechanisms by which high-fat diet induced peripheral signals affect the hypothalamic arcuate nucleus remain largely unknown. In this chapter, besides lipids and leptin, the role of glucose and insulin on specialized fuel-sensing neurons of hypothalamic neuronal circuits has been debated.

Effects of MetAP2 inhibition on hyperphagia and body weight in Prader-Willi syndrome: A randomized, double-blind, placebo-controlled trial.

AIMS: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. MATERIALS AND METHODS: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. RESULTS: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo. CONCLUSIONS: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.

Dietary calcium supplementation in adult rats reverts brown adipose tissue dysfunction programmed by postnatal early overfeeding.

Brown adipose tissue (BAT) dysfunction is associated with obesity and its comorbidities, such as hypertension, and the improvement of BAT function seems important for obesity management. Here we investigated the effects of dietary calcium supplementation on BAT autonomic nerve activity, sympathoadrenal function and cardiovascular parameters in adult obese rats that were raised in small litters (SL group). Three days after birth, SL litters were adjusted to three pups to induce early overfeeding. The control group remained with 10 pups/litter until weaning (NL group). At PN120, the SL group was randomly divided into the following: rats fed with standard chow (SL) and rats fed with dietary calcium carbonate supplementation (SL-Ca, 10g/kg chow). Animals were killed either at PN120 or PN180. At both ages, SL rats had higher BAT autonomic nervous system activity, mass and adipocyte area, as well as increased heart rate and blood pressure (systolic and diastolic); 2 months of calcium supplementation normalized these parameters. At PN180 only, UCP1 and TRß1 in BAT were decreased in SL rats. These changes were also prevented by calcium treatment. Also at PN180, the SL group presented higher tyrosine hydroxylase and adrenal catecholamine contents, as well as lower hypothalamic POMC and MC4R contents. Calcium supplementation did not revert these alterations. Thus, we demonstrated that dietary calcium supplementation was able to improve cardiovascular parameters and BAT thermogenesis capacity in adult animals that were early overfed during lactation.

Overconsumption of Energy and Excessive Discretionary Food Intake Inflates Dietary Greenhouse Gas Emissions in Australia.

Population dietary guidelines have started to include information about the environmental impacts of food choices, but more quantifiable evidence is needed, particularly about the impacts associated with discretionary foods. This paper utilised the 2011-2012 Australian Health Survey food intake data along with a highly disaggregated input-output model to estimate the greenhouse gas emissions (GHGe) of Australians' dietary intake, and compare current patterns of eating which vary in diet quality and GHGe to the recommended diet. The average dietary GHGe were 18.72 ± 12.06 and 13.73 ± 8.72 kg CO2e/day for male and female adults, respectively. The correlation between total energy and GHGe was r = 0.54 (p < 0.001). Core foods contributed 68.4% and discretionary foods 29.4%. Within core foods, fresh meat and alternatives (33.9%) was the greatest contributor. The modelling of current dietary patterns showed the contribution of discretionary foods to GHGe was 121% greater in the average diet and 307% greater in the "lower quality, higher GHGe" diet compared to the recommended diet. Reducing discretionary food intake would allow for small increases in emissions from core foods (in particular vegetables, dairy and grains), thereby providing a nutritional benefit at little environmental expense. Public health messages that promote healthy eating, eating to one's energy needs and improved diet quality will also contribute to lowering GHGe.

Effects of sugar rich diet on brain serotonin, hyperphagia and anxiety in animal model of both genders.

Lower levels of 5-hydroxytryptamine (5-HT; serotonin) in the brain elicit sugar craving, while ingestion of sugar rich diet improves mood and alleviates anxiety. Gender differences occur not only in brain serotonin metabolism but also in a serotonin mediated functional responses. The present study was therefore designed to investigate gender related differences on the effects of long term consumption of sugar rich diet on the metabolism of serotonin in the hypothalamus and whole brain which may be relevant with the hyperphagic and anxiety reducing effects of sugar rich diet. Male and female rats were fed freely on a sugar rich diet for five weeks. Hyperphagic effects were monitored by measuring total food intake and body weights changes during the intervention. Anxiolytic effects of sugar rich diet was monitored in light-dark transition test. The results show that ingestion of sugar rich diet decreased serotonin metabolism more in female than male rats. Anxiolytic effects were elicited only in male rats. Hyperphagia was comparable in both male and female rats. Finings would help in understanding the role of sugar rich diet-induced greater decreases of serotonin in sweet craving in women during stress.

Short-term feeding at the wrong time is sufficient to desynchronize peripheral clocks and induce obesity with hyperphagia, physical inactivity and metabolic disorders in mice.

BACKGROUND: The circadian clock regulates various physiological and behavioral rhythms such as feeding and locomotor activity. Feeding at unusual times of the day (inactive phase) is thought to be associated with obesity and metabolic disorders in experimental animals and in humans. OBJECTIVE: The present study aimed to determine the underlying mechanisms through which time-of-day-dependent feeding influences metabolic homeostasis. METHODS: We compared food consumption, wheel-running activity, core body temperature, hormonal and metabolic variables in blood, lipid accumulation in the liver, circadian expression of clock and metabolic genes in peripheral tissues, and body weight gain between mice fed only during the sleep phase (DF, daytime feeding) and those fed only during the active phase (NF, nighttime feeding). All mice were fed with the same high-fat high-sucrose diet throughout the experiment. To the best of our knowledge, this is the first study to examine the metabolic effects of time-imposed restricted feeding (RF) in mice with free access to a running wheel. RESULTS: After one week of RF, DF mice gained more weight and developed hyperphagia, higher feed efficiency and more adiposity than NF mice. The daily amount of running on the wheel was rapidly and obviously reduced by DF, which might have been the result of time-of-day-dependent hypothermia. The amount of daily food consumption and hypothalamic mRNA expression of orexigenic neuropeptide Y and agouti-related protein were significantly higher in DF, than in NF mice, although levels of plasma leptin that fluctuate in an RF-dependent circadian manner, were significantly higher in DF mice. These findings suggested that the DF induced leptin resistance. The circadian phases of plasma insulin and ghrelin were synchronized to RF, although the corticosterone phase was unaffected. Peak levels of plasma insulin were remarkably higher in DF mice, although HOMA-IR was identical between the two groups. Significantly more free fatty acids, triglycerides and cholesterol accumulated in the livers of DF, than NF mice, which resulted from the increased expression of lipogenic genes such as Scd1, Acaca, and Fasn. Temporal expression of circadian clock genes became synchronized to RF in the liver but not in skeletal muscle, suggesting that uncoupling metabolic rhythms between the liver and skeletal muscle also contribute to DF-induced adiposity. CONCLUSION: Feeding at an unusual time of day (inactive phase) desynchronizes peripheral clocks and causes obesity and metabolic disorders by inducing leptin resistance, hyperphagia, physical inactivity, hepatic fat accumulation and adiposity.

Reduced reward-driven eating accounts for the impact of a mindfulness-based diet and exercise intervention on weight loss: Data from the SHINE randomized controlled trial.

Many individuals with obesity report over eating despite intentions to maintain or lose weight. Two barriers to long-term weight loss are reward-driven eating, which is characterized by a lack of control over eating, a preoccupation with food, and a lack of satiety; and psychological stress. Mindfulness training may address these barriers by promoting awareness of hunger and satiety cues, self-regulatory control, and stress reduction. We examined these two barriers as potential mediators of weight loss in the Supporting Health by Integrating Nutrition and Exercise (SHINE) randomized controlled trial, which compared the effects of a 5.5-month diet and exercise intervention with or without mindfulness training on weight loss among adults with obesity. Intention-to-treat multiple mediation models tested whether post-intervention reward-driven eating and psychological stress mediated the impact of intervention arm on weight loss at 12- and 18-months post-baseline among 194 adults with obesity (BMI: 30-45). Mindfulness (relative to control) participants had significant reductions in reward-driven eating at 6 months (post-intervention), which, in turn, predicted weight loss at 12 months. Post-intervention reward-driven eating mediated 47.1% of the total intervention arm effect on weight loss at 12 months [ß = -0.06, SE(ß) = 0.03, p = .030, 95% CI (-0.12, -0.01)]. This mediated effect was reduced when predicting weight loss at 18 months (p = .396), accounting for 23.0% of the total intervention effect, despite similar weight loss at 12 months. Psychological stress did not mediate the effect of intervention arm on weight loss at 12 or 18 months. In conclusion, reducing reward-driven eating, which can be achieved using a diet and exercise intervention that includes mindfulness training, may promote weight loss (clinicaltrials.gov registration: NCT00960414).

Programmed hyperphagia in offspring of obese dams: Altered expression of hypothalamic nutrient sensors, neurogenic factors and epigenetic modulators.

Maternal overnutrition results in programmed offspring obesity, mediated in part, by hyperphagia. This is remarkably similar to the effects of maternal undernutrition on offspring hyperphagia and obesity. In view of the marked differences in the energy environment of the over and under-nutrition exposures, we studied the expression of select epigenetic modifiers associated with energy imbalance including neurogenic factors and appetite/satiety neuropeptides which are indicative of neurogenic differentiation. HF offspring were exposed to maternal overnutrition (high fat diet; HF) during pregnancy and lactation. We determined the protein expression of energy sensors (mTOR, pAMPK), epigenetic factors (DNA methylase, DNMT1; histone deacetylase, SIRT1/HDAC1), neurogenic factors (Hes1, Mash1, Ngn3) and appetite/satiety neuropeptides (AgRP/POMC) in newborn hypothalamus and adult arcuate nucleus (ARC). Despite maternal obesity, male offspring born to obese dams had similar body weight at birth as Controls. However, when nursed by the same dams, male offspring of obese dams exhibited marked adiposity. At 1 day of age, HF newborn males had significantly decreased energy sensors, DNMT1 including Hes1 and Mash1, which may impact neuroprogenitor cell proliferation and differentiation. This is consistent with increased AgRP in HF newborns. At 6 months of age, HF adult males had significantly increased energy sensors and decreased histone deactylases. In addition, the persistent decreased Hes1, Mash1 as well as Ngn3 are consistent with increased AgRP and decreased POMC. Thus, altered energy sensors and epigenetic responses which modulate gene expression and adult neuronal differentiation may contribute to hyperphagia and obesity in HF male offspring.

Resveratrol treatment rescues hyperleptinemia and improves hypothalamic leptin signaling programmed by maternal high-fat diet in rats.

PURPOSE: Perinatal high-fat diet is associated with obesity and metabolic diseases in adult offspring. Resveratrol has been shown to exert antioxidant and anti-obesity actions. However, the effects of resveratrol on leptinemia and leptin signaling are still unknown as well as whether resveratrol treatment can improve metabolic outcomes programmed by maternal high-fat diet. We hypothesize that resveratrol treatment in male rats programmed by high-fat diet would decrease body weight and food intake, and leptinemia with changes in central leptin signaling. METHODS: Female Wistar rats were divided into two groups: control group (C), which received a standard diet containing 9 % of the calories as fat, and high-fat group (HF), which received a diet containing 28 % of the calories as fat. Dams were fed in C or HF diet during 8 weeks before mating and throughout gestation and lactation. C and HF male offspring received standard diet throughout life. From 150 until 180 days of age, offspring received resveratrol (30 mg/Kg body weight/day) or vehicle (carboxymethylcellulose). RESULTS: HF offspring had increased body weight, hyperphagia and increased subcutaneous and visceral fat mass compared to controls, and resveratrol treatment decreased adiposity. HF offspring had increased leptinemia as well as increased SOCS3 in the arcuate nucleus of the hypothalamus, which suggest central leptin resistance. Resveratrol treatment rescued leptinemia and increased p-STAT3 content in the hypothalamus with no changes in SOCS3, suggesting improvement in leptin signaling. CONCLUSIONS: Collectively, our data suggest that resveratrol could reverse hyperleptinemia and improve central leptin action in adult offspring from HF mothers attenuating obesity.

Hypothalamic Non-AgRP, Non-POMC GABAergic Neurons Are Required for Postweaning Feeding and NPY Hyperphagia.

The hypothalamus is critical for feeding and body weight regulation. Prevailing studies focus on hypothalamic neurons that are defined by selectively expressing transcription factors or neuropeptides including those expressing proopiomelanocortin (POMC) and agouti-related peptides (AgRP). The Cre expression driven by the pancreas-duodenum homeobox 1 promoter is abundant in several hypothalamic nuclei but not in AgRP or POMC neurons. Using this line, we generated mice with disruption of GABA release from a major subset of non-POMC, non-AgRP GABAergic neurons in the hypothalamus. These mice exhibited a reduction in postweaning feeding and growth, and disrupted hyperphagic responses to NPY. Disruption of GABA release severely diminished GABAergic input to the paraventricular hypothalamic nucleus (PVH). Furthermore, disruption of GABA-A receptor function in the PVH also reduced postweaning feeding and blunted NPY-induced hyperphagia. Given the limited knowledge on postweaning feeding, our results are significant in identifying GABA release from a major subset of less appreciated hypothalamic neurons as a key mediator for postweaning feeding and NPY hyperphagia, and the PVH as one major downstream site that contributes significantly to the GABA action. Significance statement: Prevalent studies on feeding in the hypothalamus focus on well characterized, selective groups neurons [e.g., proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons], and as a result, the role of the majority of other hypothalamic neurons is largely neglected. Here, we demonstrated an important role for GABAergic projections from non-POMC non-AgRP neurons to the paraventricular hypothalamic nucleus in promoting postweaning (mainly nocturnal) feeding and mediating NPY-induced hyperphagia. Thus, these results signify an importance to study those yet to be defined hypothalamic neurons in the regulation of energy balance and reveal a neural basis for postweaning (nocturnal) feeding and NPY-mediated hyperphagia.