Reduction In Daily Food Intake Research Articles

Dynamic Hydration and Viscosity Control of Konjac Glucomannan Enhance Long-Term Antiobesity Effects by Reducing Food Intake in High-Fat-Diet-Fed Mice.

The purpose of this study was to investigate the necessity and importance of dynamic hydration rate and ultimate viscosity control of konjac glucomannan (KGM) for long-term antiobesity effects in C57BL/6J mice on high-fat (HF) diets. KGM supplementation effectively attenuated HF-diet-induced increases in body and tissue weights. The hydration rate and viscosity changes of KGM in the digestive tract were found to have marked impacts on antiobesity effects. KGM with medium hydration and viscosity slowed gastric emptying and intestinal transit, leading to prolonged presence in the lower ileum, increased satiety-related hormones (GLP-1 and PYY), and an 18.27% reduction in daily food intake over 10 weeks (p < 0.05). This resulted in the greatest reduction in weight gain among HF-fed mice. In contrast, KGM with faster hydration and higher viscosity provided only short-term satiety due to rapid dilution. Furthermore, KGM improved metabolic health and altered glycolipid metabolism gene transcription while enriching beneficial gut bacteria; however, no significant differences were observed among the KGM groups in these effects. These findings highlight that synchronizing KGM's hydration rate and viscosity with digestive processes is crucial for regulating satiety and achieving long-term weight loss.

Fasting - a potent modern therapy

Therapeutic fasting has found its way into modern medicine in the last decade through a multitude of experimental work and animal studies as well as increasing clinical research. It is a procedure with a tradition dating back thousands of years and thus comes with a variety of different practices. What they all have in common, is the reduction of daily food intake for a limited period of time. This has a variety of effects on metabolism, cells and organ systems, which can make it a potent tool in medical practice.

Process-oriented impacts of microplastic fibers on behavior and histology of fish

Microplastic pollution has raised global concern for its hazards to biota. To determine the direct impact of microplastics during their contact with fish, we exposed goldfish (Carassius auratus) to 100 and 1000 items/L waterborne microplastic fibers in the short- and long-term. In the presence of 1000 items/L of microplastic fibers, the coughing behavior of fish increased significantly after 2 h of exposure. Predatory behaviors decreased significantly by 53.0% after 45 d of exposure, and the reduction in daily food intake was negatively related to exposure duration in the 1000 items/L group. In addition, microplastic fibers stimulated dynamic mucus secretion across different fish tissues during the different processes evaluated in this study, with 30.0% and 62.9% overall increases in the secretory capacity of mucus cells in the 100 and 1000 items/L groups, respectively. These behavioral and histological alterations were derived from the ventilation, feeding, and swimming processes of goldfish. We regarded these changes as process-oriented impacts, suggesting the effects of microplastics on fish and how fish cope with microplastics.

Yo‐Yo Diet Has Adverse Effects on Cardiac Function and Insulin Sensitivity in Female Fischer Rats

IntroductionWe have shown in female rats on a severe food restricted (sFR) diet that rapid body weight (BW) loss is associated with long term cardiovascular dysfunction months after BW has returned to normal levels due to refeeding. To further investigate the long term adverse cardiovascular effects of a sFR diet, we studied a model of BW cycling in which BW is rapidly lost, gained back, then lost again, since BW cycling is common in individuals who voluntarily diet (e.g., yo‐yo dieting) or those exposed involuntarily to inadequate caloric consumption (e.g., due to poverty).MethodsThree‐month‐old female Fischer rats were divided into 2 groups and maintained on a control (CT; regular chow ad libitum for duration of study, n=8) or sFR (60% reduction of daily food intake, n=8) diet for 2 weeks. The sFR rats then received regular chow ad libitum for 3 weeks. This cycle of 2 weeks sFR diet plus 3 weeks of refeeding (c‐sFR) was repeated twice more. Cardiac and renal function were assessed using ultrasound and insulin sensitivity was evaluated using the homeostatic model assessment of insulin resistance (HOMA‐IR) index.ResultsDuring the 1st c‐sFR, rats lost 20% of their BW after 14 days on the sFR diet; however, their BW rapidly returned to CT levels during the 3‐week refeeding period. The 2nd and 3rd c‐sFR led to similar BW losses (20% and 19%, respectively). No differences were observed in mean arterial pressure (MAP) and heart rate (HR) after the 3rd c‐sFR compared to CT rats. However, the c‐sFR rats (n=4) showed 20‐40% reductions in renal artery flow (mm/s: CT, 295±12 vs c‐sFR, 235±6; p&lt;0.05), cardiac output (mL/min: CT, 43±2 vs c‐sFR, 31±3; p&lt;0.05) and stroke volume (mL: CT, 153±4 vs c‐sFR, 89±10; p&lt;0.05) while the HOMA‐IR index was 2.6‐fold higher (AU: CT, 3±0.8 vs c‐sFR, 8±1.9; p&lt;0.05) compared to CT rats (n=4).ConclusionDespite normalization of BW, MAP and HR after 3 c‐sFR periods, c‐sFR rats had reduced heart and kidney function and higher insulin resistance when compared to CT rats. This study suggests individuals who engage in yo‐yo dieting or have experienced BW cycling due to inadequate food intake from other causes (e.g., very low food security, war, natural disasters) are at increased risk for developing cardio‐metabolic disease.

Persistent Renin-Angiotensin System Sensitization Months After Body Weight Recovery From Severe Food Restriction in Female Fischer Rats.

BackgroundPrior exposure to periods of severe food restriction (sFR) is associated with increased risk of developing hypertension and cardiovascular disease later in life.Methods and ResultsTo investigate the mechanism of these long‐term adverse effects of sFR, 4‐month‐old female Fischer rats were divided in 2 groups and maintained on a normal diet ad libitum (control) or on an sFR diet with 60% reduction in daily food intake for 2 weeks that resulted in a 15% reduction in body weight. After the 2‐week sFR period ended, both groups received normal chow ad libitum for 3 months. Within 2 weeks after refeeding was initiated in the sFR group, body weight was restored to control levels; however, plasma angiotensinogen (1.3‐fold; P<0.05), Ang‐[1‐8] (2.0‐fold; P<0.05), and angiotensin‐converting enzyme activity (1.1‐fold; P<0.01) were all elevated 3 months after refeeding. Angiotensin type 1 receptor activity was also increased as evidenced by augmented pressor responses to angiotensin‐[1‐8] (P<0.01) and depressor responses to the angiotensin type 1 receptor antagonist, losartan (P<0.01) in the sFR group.ConclusionsThese results indicate that sensitization of the renin‐angiotensin system persisted months after the sFR period ended. These findings may have implications for women who voluntarily or involuntarily experience an extended period of sFR and thus may be at increased risk of developing cardiovascular disease through sensitization of the renin‐angiotensin system even though their body weight, mean arterial pressure, and heart rate appear normal.

Western diet (WD) activates pancreatic Toll‐like receptor 4 (TLR4) signaling in female rats: a potential mechanism of WD‐induced insulin resistance

BackgroundOverconsumption of a WD, a high‐fat and high‐sugar diet, has plagued the United States contributing to the widespread prevalence of type 2 diabetes (T2DM). Insulin resistance (IR) plays a key role in the development of T2DM and is a consistent finding among T2DM patients. The pathogenesis of IR, however, is not well understood. Based on recent evidence that inflammation precedes IR, and previous findings from our lab showing involvement of Toll‐like receptor 4 (TLR4) signaling in diabetic vascular inflammation, we hypothesize that WD leads to pancreatic inflammation through TLR4 signaling activation, contributing to IR.MethodsOur lab has established a model of a WD‐induced metabolic syndrome and IR in female rats. Eight‐week old female Wistar rats were randomized into two experimental groups: Control (n = 9) and WD group (n = 16). The control group received a regular chow diet (5% fat, 48.7% carbohydrates [3.2% sucrose], and 24.1% protein), while the WD group received a WD (40% fat, 43% carbohydrates [34% sucrose], 17% protein), for 28 weeks. Body weight and food consumption were measured weekly. Lipid and glucose metabolism, and intraperitoneal glucose tolerance tests (IPGTT) were measured. Quantitative IR was assessed using Homeostasis Model Assessment of Insulin Resistance (HOMA‐IR), while functional beta cell capacity was assessed via HOMA‐B calculation. At the terminal experiments, pancreas’ were isolated for molecular (TLR4 signaling) and histological (hematoxylin and eosin, H&amp;E) analysis.ResultsWD group exhibited greater body weight (415.1 ± 30.9 vs. 323.0 ± 24.0 g controls, p&lt;0.01), and increased daily caloric consumption (130.5 ± 7.36 vs.110.7 ± 7.0 kcals controls, p&lt;0.05) in spite of a significant reduction in daily food intake (23.7 ± 1.5 vs. 31.5 ± 1.8 g controls, p&lt;0.01). WD negatively interfered in the glucose metabolism as evidenced by increased blood glucose area under the curve during IPGTT (17531.8 ± 574.3 vs. 12381.25 ± 1480.6 a.u. controls, p&lt;0.001). IR in the WD group was confirmed by increased HOMA‐IR (8.09 ± 1.90 vs. 2.05 ± .042 a.u. controls, p&lt;0.001), which was accompanied by hyperinsulinemia (0.93 ± 0.1 vs. 0.30 ± 0.09 mg/dL controls, p&lt;0.01). No changes were observed in the HOMA‐B, suggesting that β cells remain functional. Moreover, no evidence of vacuolation, irregular outlining and size of the Langerhans islets, which are all markers of β cell dysfunction, were observed in the H&amp;E stained pancreatic section from the WD group. Pancreatic inflammation in the WD group was confirmed by a 42% increase in TNF‐α expression (p&lt;0.05), an inflammatory marker. Strikingly, pancreatic TLR4 (1.8‐fold increased, p&lt;0.05) and its downstream molecule TNF‐receptor associated factor 6 (TRAF6) (3.1‐fold increased, p&lt;0.001) were markedly upregulated in the WD group in comparison to controls, indicating TLR4/TRAF6 signaling activation in the pancreas.ConclusionOur findings suggest that a WD can induce IR along with activation of pancreatic TLR4 signaling‐related inflammation. These results can provide new insights into how high fat and fat sugar diet choices can causes inflammation in the pancreas.Support or Funding InformationNIH

The Effects of Calorie Restriction and Exercise on Age-Related Alterations in Corpus Cavernosum.

BackgroundAging is an important risk factor for erectile dysfunction (ED). Both calorie restriction (CR) and physical exercise (PE) have been established as a non-medical method for the improvement of detrimental changes in aging. It is well documented that both CR and PE influence on sympathetic and parasympathetic systems; however, there are few studies on non-adrenergic non-cholinergic pathways. This study aims to investigate the NO-mediated mechanisms of CR and PE on corpus cavernosum in aged rats.Materials and Methods3 and 15 month-old rats were divided into five experimental groups: young rats fed ad libitum (Y-C), aged rats fed ad libitum (O-S), aged rats with CR (O-CR), aged rats with PE (O-PE), and aged rats with CR and PE (O-CR-PE). CR was applied to animals as a 40% reduction of daily food intake for 6 weeks. PE was moderate swimming at 30 min at 3 days/week. The effects of CR and PE were evaluated by histologic, biologic, and in-vitro tissue bath studies.ResultsThe outcomes in CR and PE groups (characterized by decreased nitrosative damage together with increased antioxidant capacity) were improved in comparison to the O-S. Apoptotic biomarkers were also lower and both endothelial and smooth muscle cell’ functions were preserved too. There was no statistical difference between apoptosis, antioxidant capacity, and nitrosative damage parameters. Contractile responses to phenylephrine and relaxation responses to carbachol were: O-CR > O-PE > O-CR-PE. In these groups, NOS protein levels determined by western-blot were: eNOS: O-CR = O-CR + PE > O-PE; iNOS: O-CR = O-PE > O-CR-PE; nNOS: O-PE > O-CR-PE > O-CR.ConclusionIn our study, both CR and PE prevented age-related changes in the corpus cavernosum of rats. Reducing nitrosative damage in the neurovascular structure was the main mechanism. CR and exercise restored the endothelial and smooth muscle cells in corpus cavernosum by decreasing apoptosis. The mechanism of enhancing functional response in corpus cavernosum with CR was the improvement of endothelial function via eNOS activation however it involves increases in the NO-cGMP signaling pathway by an endothelium-independent mechanism with PE. This might be a direct stimulation of smooth muscle cells by NO, which released from the cavernous nerve endings via nNOS activation.

Dietary Restriction Suppresses Steatosis-Associated Hepatic Tumorigenesis in Hepatitis C Virus Core Gene Transgenic Mice

Background and Aims: Dietary restriction (DR) is a preventive strategy for obesity, metabolic syndrome, cardiovascular disease, and diabetes. Although an interconnection between obesity, metabolic syndrome, fatty liver, and hepatocellular carcinoma has been documented, the mechanism and impact of DR on steatosis-derived hepatocarcinogenesis are not fully understood. This study aimed to evaluate whether DR can prevent hepatic tumorigenesis. Methods: Male hepatitis C virus core gene transgenic (HCVcpTg) mice that develop spontaneous age-dependent insulin resistance, hepatic steatosis, and ensuing liver tumor development without apparent hepatic fibrosis, were fed with either a control diet ad libitum (control group) or 70% of the same control diet (DR group) for 15 months, and liver phenotypes were investigated. Results: DR significantly reduced the number and volume of liver tumors. DR attenuated hepatic oxidative and endoplasmic reticulum stress and markedly suppressed nuclear factor-κB, signal transducer and activator of transcription 3 (STAT3) and STAT5, and phosphorylation of extracellular signal-regulated kinase, leading to downregulation of several pro-oncogenic mediators, such as cyclin D1. Serum insulin and insulin-like growth factor 1 levels, as well as hepatic expression of insulin receptor substrate 1/2, phosphatidylinositol-3 kinase, and serine/threonine-protein kinase AKT, were downregulated by DR. A transcriptome analysis revealed that STAT3 signaling and lipogenesis were the most suppressed hepatocarcinogenic pathways affected by DR. Additionally, DR stimulated autophagy and p62/sequestosome 1 degradation, enhanced phosphorylation of AMP-activated protein kinase α, increased fibroblast growth factor 21 expression, and attenuated expression of senescence-associated secretory phenotypes. Conclusion: DR suppressed steatosis-associated hepatic tumorigenesis in HCVcpTg mice, mainly due to attenuation of pathways involved in inflammation, cellular stress, cell proliferation, insulin signaling, and senescence. These findings support the notion that persistent 30% reduction of daily food intake is beneficial for preventing steatosis-associated hepatocarcinogenesis caused by HCV core protein.

Long‐term consequences of severe food restriction on the heart of female Fischer rats

IntroductionIndividuals under voluntary (e.g., anorexia, crash diets) or involuntary (e.g., very low food security) severe food restriction (sFR) are at increased risk for developing cardiovascular disease during the sFR period and also long term well after the sFR period has ended. During the sFR period patients present long QT interval, arrhythmia, hypotension and bradycardia and sometimes death, which is primarily due to heart failure. Unfortunately, Little is known, however, almost nothing is known about the heart function when these individuals recoveries the body weight. Cardiovascular disease due to earlier exposure to sFR is an underappreciated and understudied problem and there are no Aim: ‐consequencesof sFR on heart structure and function known therapeutic strategies designed to prevent or reverse the increased risk after recovery from the sFR period(s).MethodsFemale Fischer rats with 3‐month‐old were divided in a control (CT) (ad libitum regular chow; n=18) and sFR (60% reduction of daily food intake, n=18) group. After 2 weeks all rats received regular chow ad libitum for 3 months. The control and sFR rats were then divided into three groups each and infused with vehicle (n=8), in a bolus infusion of angiotensin II (400ng/Kg – 0.2mL; n=6), or subjected to ischemia‐reperfusion using a Langendorff preparation (n=4). At the end of the experiment, the rats were sacrificed and the hearts were removed for histology.ResultsAfter 14 of sFR body weight was reduced by 18%, Mean arterial pressure (p=0.03), heart rate (p=0.03) and wet heart weight (p=0.009) were reduced. After 3 mo of refeeding, body weight, MAP, HR, and wet heart weight were indistinguishable from the control animals. Despite normalization of some parameters,, 3 months of refeeding, analysis of H&amp;E stained myocardium tissue in vehicle‐treated rats revealed that parallel orientation of myofiber and clear striations present in normal cardiomyocytes were lost in sFR‐refed animals indicating severe cardiac damage. Uneven blood‐filling of the vessels of the microcirculatory and prominent interstitial edema of the myocardium was observed. The cardiomyocytes were polymorphic and single cardiomyocytes also found to be atrophied. Infusion of angiotensin II to sFR‐refed animals, but not to control animals, resulted in the occurrence of focal necrotic lesions causing by multiple contractures of cardiomyocytes, indicating cardiomyocytes had disrupted of calcium homeostasis and increased calcium sensitivityof sFR‐refed animals. The magnitude of ischemia/reperfusion‐induced damage was also greater in sFR‐refed animals compared to control animals in Langendorff preparations. After ischemia/reperfusion injury, along with deeply eosinophilic myofibers, large amounts of necrotic cardiomyocytes were found in sFR‐refed rats, but not in control.ConclusionDespite normalization of body weight, blood pressure, heart rate and wet heart weight after 3 months of refeeding, the hearts from animals subjected to severe food restriction are severely damaged. These findings suggest individuals who have recovered from prior exposure to a period of sFR are at increased risk of developing cardiovascular disease.Support or Funding InformationNIH 1R01HL119380 (KS)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

3486 Sex Differences in the Effects of Severe Food Restriction on Electrolyte Balance

OBJECTIVES/SPECIFIC AIMS: The goal of this study was to determine if there are any sex differences in the pathophysiological effects of sFR. METHODS/STUDY POPULATION: Male Fischer rats (4-month-old) were maintained on a control (CT) (ad libitum regular chow; n=8) or sFR (60% reduction of daily food intake, n=8) diet for 2 weeks. On days 1, 2, 3 and 14, the rats were placed in metabolic cages for food and water intake and 24-hour urine collection. Body weight (BW) is measured daily. After 2 weeks, the animals are given free access to normal chow for 3 months. Short-term and long-term effects of sFR on blood pressure and heart rate will be measured. RESULTS/ANTICIPATED RESULTS: After 2 weeks, the male CT group gained 7% BW (p &lt;0.05), while BW in the sFR males was reduced by 12% (p&lt;0.05 vs. CT). In contrast, female controls did not gain BW while the sFR females lost 18% of their BW. Water intake was reduced by 35%, which was similar to the reduction in females (p=0.18). The hematocrit of sFR male rats was higher (51.1%) than the CT group (45.2%, p&lt;0.05), which was most likely due to the 6% reduction in plasma volume. A similar effect on hematocrit was observed in sRF females. Similarly, also to female rats, sFR had no effect on Na+ and K+ plasma or urine concentrations by day 14 in the male rats. DISCUSSION/SIGNIFICANCE OF IMPACT: sFR has similar effects on electrolyte balance in males and females. Ongoing studies will determine if there is any sex difference in the effects of sFR on blood pressure, heart rate and susceptibility to hypertension and cardiac injury.

Torpor reduces predation risk by compensating for the energetic cost of antipredator foraging behaviours.

Foraging activity is needed for energy intake but increases the risk of predation, and antipredator behavioural responses, such as reduced activity, generally reduce energy intake. Hence, the mortality and indirect effects of predation risk are dependent on the energy requirements of prey. Torpor, a controlled reduction in resting metabolism and body temperature, is a common energy-saving mechanism of small mammals that enhances their resistance to starvation. Here we test the hypothesis that torpor could also reduce predation risk by compensating for the energetic cost of antipredator behaviours. We measured the foraging behaviour and body temperature of house mice in response to manipulation of perceived predation risk by adjusting levels of ground cover and starvation risk by 24 h food withdrawal every third day. We found that a voluntary reduction in daily food intake in response to lower cover (high predation risk) was matched by the extent of a daily reduction in body temperature. Our study provides the first experimental evidence of a close link between energy-saving torpor responses to starvation risk and behavioural responses to perceived predation risk. By reducing the risk of starvation, torpor can facilitate stronger antipredator behaviours. These results highlight the interplay between the capacity for reducing metabolic energy expenditure, optimal decisions about foraging behaviour and the life-history ecology of prey.

A Role of Central NELL2 in the Regulation of Feeding Behavior in Rats.

A brain-enriched secreting signal peptide, NELL2, has been suggested to play multiple roles in the development, survival, and activity of neurons in mammal. We investigated here a possible involvement of central NELL2 in regulating feeding behavior and metabolism. In situ hybridization and an im-munohistochemical approach were used to determine expression of NELL2 as well as its colocalization with proopiomelanocortin (POMC) and neuropeptide Y (NPY) in the rat hypothalamus. To investigate the effect of NELL2 on feeding behavior, 2 nmole of antisense NELL2 oligodeoxynucleotide was administered into the lateral ventricle of adult male rat brains for 6 consecutive days, and changes in daily body weight, food, and water intake were monitored. Metabolic state-dependent NELL2 expression in the hypothalamus was tested in vivo using a fasting model. NELL2 was noticeably expressed in the hypothalamic nuclei controlling feeding behavior. Furthermore, all arcuatic POMC and NPY positive neurons produced NELL2. The NELL2 gene expression in the hypothalamus was up-regulated by fasting. However, NELL2 did not affect POMC and NPY gene expression in the hypothalamus. A blockade of NELL2 production in the hypothalamus led to a reduction in daily food intake, followed by a loss in body weight without a change in daily water intake in normal diet condition. NELL2 did not affect short-term hunger dependent appetite behavior. Our data suggests that hypothalamic NELL2 is associated with appetite behavior, and thus central NELL2 could be a new therapeutic target for obesity.

Robust Reductions of Excess Weight and Hyperphagia by Beloranib in Rat Models of Genetic and Hypothalamic Obesity.

Hypothalamic lesions or deficient melanocortin (MC) signaling via MC4 receptor (MC4r) mutations often lead to hyperphagia and severe treatment-resistant obesity. We tested the methionine aminopeptidase 2-inhibitor beloranib (ZGN-440) in 2 male rat models of obesity, one modeling hypothalamic obesity with a combined medial hypothalamic lesion (CMHL) and the other modeling a monogenic form of obesity with MC4r mutations (MC4r knockout [MC4rKO]). In CMHL rats (age 3 months), postsurgery excess weight gain was significantly inhibited (ZGN-440, 0.2 ± 0.7 g/d; vehicle, 3.8 ± 0.6 g/d; P < 0.001) during 12 days of ZGN-440 treatment (0.1 mg/kg daily subcutaneously) together with a 30% reduction of daily food intake vs vehicle injection. In addition, ZGN-440 treatment improved glucose tolerance and reduced plasma insulin, and circulating levels of α-melanocyte stimulating hormone were increased. Serum lipid levels did not differ significantly in ZGN-440-treated vs vehicle-treated rats. Similar results were found in MC4rKO rats: ZGN-440 treatment (14-21 d) was associated with significant reductions of body weight gain (MC4rKO, -1.7 ± 0.6 vs 2.8 ± 0.4 g/d; lean wild-type controls, -0.7 ± 0.2 vs 1.7 ± 0.7 g/d; ZGN-440 vs vehicle, respectively), reduction of food intake (MC4rKO, -28%; lean controls, -7.5%), and insulin resistance, whereas circulating levels of interleukin-1β did not change. In both obesity models, body temperature and locomotor activity were not affected by ZGN-440 treatment. In conclusion, the robust reduction of body weight in response to ZGN-440 observed in rats with severe obesity is related to a strong reduction of food intake that is likely related to changes in the central regulation of feeding.

PASylation of Murine Leptin Leads to Extended Plasma Half-Life and Enhanced in Vivo Efficacy.

Leptin plays a central role in the control of energy homeostasis and appetite and, thus, has attracted attention for therapeutic approaches in spite of its limited pharmacological activity owing to the very short circulation in the body. To improve drug delivery and prolong plasma half-life, we have fused murine leptin with Pro/Ala/Ser (PAS) polypeptides of up to 600 residues, which adopt random coil conformation with expanded hydrodynamic volume in solution and, consequently, retard kidney filtration in a similar manner as polyethylene glycol (PEG). Relative to unmodified leptin, size exclusion chromatography and dynamic light scattering revealed an approximately 21-fold increase in apparent size and a much larger molecular diameter of around 18 nm for PAS(600)-leptin. High receptor-binding activity for all PASylated leptin versions was confirmed in BIAcore measurements and cell-based dual-luciferase assays. Pharmacokinetic studies in mice revealed a much extended plasma half-life after ip injection, from 26 min for the unmodified leptin to 19.6 h for the PAS(600) fusion. In vivo activity was investigated after single ip injection of equimolar doses of each leptin version. Strongly increased and prolonged hypothalamic STAT3 phosphorylation was detected for PAS(600)-leptin. Also, a reduction in daily food intake by up to 60% as well as loss in body weight of >10% lasting for >5 days was observed, whereas unmodified leptin was merely effective for 1 day. Notably, application of a PASylated superactive mouse leptin antagonist (SMLA) led to the opposite effects. Thus, PASylated leptin not only provides a promising reagent to study its physiological role in vivo but also may offer a superior drug candidate for clinical therapy.

Adult‐onset obesity induced by early life overnutrition could be reversed by caloric restriction

Overnutrition during the suckling period (small litter, SL) results in the development of adult‐onset obesity. The aim of the study was to investigate if caloric restriction (CR) in the postweaning period can reverse this phenomenon. The control litter (CL) had 12 pups/dam and SL had 3 male pups/dam from the postnatal day 3 until 21. In the postweaning period rats consumed lab chow as indicated: (i) CL and SL groups were on ad libitum regimen up to day 140, (ii) SL/CR group received 24% reduction in daily food intake compared to SL, and (iii) SL/CR/AL group was on 24% CR up to day 94 and then switched over to ad libitum feeding. CR caused reduction in body weight gains and normalized serum glucose, insulin, and leptin levels in SL/CR and SL/CR/AL rats compared to CL. The expression of neuropeptide Y (Npy) and leptin receptor (Lepr) returned to control levels in the hypothalami from SL/CR and SL/CR/AL rats compared to CL. No differences in the expression of pro‐opiomelanocortin and insulin receptor (Insr) were observed among these groups. Altered methylation of specific CpG dinucleotides in the proximal promoter region was observed for the Npy and Insr among these groups. CR resulted in normalized metabolic phenotype and gene expression involved in controlling food intake. The results show that the CR can be a successful intervention for reversing obese phenotype induced by lactational overfeeding.Grant Funding Source: NIH DK61518

Effects of Exendin‐4 Alone and With Peptide YY3–36 on Food Intake and Body Weight in Diet‐Induced Obese Rats

Significant weight loss following Roux-en-Y gastric bypass surgery (RYGB) in obese humans correlates with enhanced secretion of anorexigenic gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY(3-36) (PYY(3-36)). Our aim here was to identify a dosing strategy for intraperitoneal (IP) infusion of GLP-1 homologue exendin-4 alone and with PYY(3-36) that produces a sustained reduction in daily food intake and body weight in diet-induced obese (DIO) rats. We tested 12 exendin-4 strategies over 10 weeks. Exendin-4 infused during the first and last 3 h of the dark period at 15-20pmol/h (0.15nmol/kg/day) produced a sustained 24 ± 1% reduction in daily food intake for 17 days, and decreased body weight by 7%. In a separate group of DIO rats, none of seven dosing strategies combining exendin-4 and PYY(3-36) produced a similar reduction in daily food intake for >10 days. The subsequent decline in efficacies of exendin-4 alone and with PYY(3-36) on food intake and body weight in each experiment suggested possible receptor downregulation and tolerance to treatments. However, when treatments were discontinued for 1 day following losses in efficacies, daily food intake significantly increased. Together, these results demonstrate that (i) intermittent IP infusion of a low dose of exendin-4 can produce a relatively prolonged reduction in daily food intake and body weight in DIO rats, (ii) co-infusion of exendin-4 and PYY(3-36) does not further prolong this response, and (iii) activation of an orexigenic mechanism gradually occurs to counteract the inhibitory effects of exendin-4 alone and with PYY(3-36) on food intake and body weight.

Lack of vasopressin does not prevent the behavioural and endocrine changes induced by chronic unpredictable stress

Vasopressin (VP) plays an important role in hypothalamo–pituitary–adrenal (HPA) axis regulation and in stress-related disorders. Our previous studies confirmed the role of VP in acute situations, where VP-deficient Brattleboro rats had less depression-like behaviour compared to animals that express VP. In this study, we test the hypothesis that VP-deficient rats are more resistant to the development of chronic HPA axis hyperactivity and depression-like symptoms after chronic unpredictable stress (CUS). Male VP-deficient Brattleboro rats were compared to their heterozygous littermates (controls). CUS consisted of different mild stimuli for 5 weeks. Elevated plus maze and forced swim test were used for behavioural characterization, while organs and blood for HPA axis parameters were collected at the end of the experiment. In controls, CUS resulted in the development of chronic stress state characterized by typical somatic (body weight reduction, thymus involution) and endocrine changes (resting plasma ACTH and corticosterone elevation and POMC mRNA elevation in anterior lobe of the pituitary). Floating time in the forced swim test was enhanced together with reduced open arm entries on elevated plus maze and a reduction in daily food intake. Unexpectedly, the lack of VP did not alter the effect of CUS on the somatic and behavioural measures, but only prevented CUS-induced corticosterone changes. In conclusion, lifelong VP-deficiency has a positive effect on corticosterone elevation following CUS but does not affect the behavioural consequences of CUS. It is likely that the interplay of several related factors, rather than an alteration in a single neuropeptide, modulates behaviour and disease pathogenesis.

Effects of different intermittent peptide YY (3-36) dosing strategies on food intake, body weight, and adiposity in diet-induced obese rats

Chronic administration of anorexigenic substances to experimental animals by injections or continuous infusion typically produces either no effect or a transient reduction in food intake and body weight. Our aim here was to identify an intermittent dosing strategy for intraperitoneal infusion of peptide YY(3-36) [PYY(3-36)] that produces a sustained reduction in daily food intake and adiposity in diet-induced obese rats. Rats (665+/-10 g body wt, 166+/-7 g body fat) with intraperitoneal catheters tethered to infusion swivels had free access to a high-fat diet. Vehicle-treated rats (n=23) had relatively stable food intake, body weight, and adiposity during the 9-wk test period. None of 15 PYY(3-36) dosing regimens administered in succession to a second group of rats (n=22) produced a sustained 15-25% reduction in daily food intake for >5 days, although body weight and adiposity were reduced across the 9-wk period by 12% (594+/-15 vs. 672+/-15 g) and 43% (96+/-7 vs. 169+/-9 g), respectively. The declining inhibitory effect of PYY(3-36) on daily food intake when the interinfusion interval was >or=3 h appeared to be due in part to an increase in food intake between infusions. The declining inhibitory effect of PYY(3-36) on daily food intake when the interinfusion interval was <3 h suggested possible receptor downregulation and tolerance to frequent PYY(3-36) administration; however, food intake significantly increased when PYY(3-36) treatments were discontinued for 1 day following apparent loss in treatment efficacies. Together, these results demonstrate the development of a potent homeostatic response to increase food intake when PYY(3-36) reduces food intake and energy reserves in diet-induced obese rats.

Salmon calcitonin reduces food intake through changes in meal sizes in male rhesus monkeys

Amylinergic mechanisms are believed to be involved in the control of appetite. This study examined the effects of the amylin agonist, salmon calcitonin, on food intake and meal patterns in adult male rhesus monkeys. Fifteen minutes before the onset of their 6-h daily feeding period, monkeys received intramuscular injections of various doses of salmon calcitonin (0.032, 0.056, 0.1, 0.32, and 1 microg/kg) or saline. Salmon calcitonin dose dependently reduced total daily and hourly food intake, with significant decreases at the 0.1, 0.32, and 1 microg/kg doses. Daily food intake was reduced by approximately 35%, 62%, and 96%, at these doses, respectively. An analysis of meal patterns revealed that size of the first meal was significantly reduced across the dose range of 0.056 to 1 microg/kg, while average meal size was reduced with the 0.32 and 1 microg/kg doses. Meal number was only affected at the 1 microg/kg dose. Repeated 5-day administration of the 0.1 microg/kg dose resulted in a reduction in daily food intake only on injection day 2, while significant reductions in food intake were observed on all five injection days with a 0.32 microg/kg dose. Daily food intake was also reduced for 1 day after the termination of the 5-day injections of the 0.32 microg/kg salmon calcitonin dose. These sustained reductions in intake were expressed through decreases in meal size. These data demonstrate that salmon calcitonin acutely and consistently decreases food intake mainly through reductions in meal sizes in nonhuman primates.

Effects of intermittent intraperitoneal infusion of salmon calcitonin on food intake and adiposity in obese rats

Chronic administration of anorexigenic substances to experimental animals by injections or continuous infusion typically produces no effect or a transient reduction in daily food intake and body weight. Our aim was to identify an intermittent dosing strategy for intraperitoneal infusion of salmon calcitonin (sCT), a homolog of amylin that produces a sustained 25-35% reduction in daily food intake and adiposity in diet-induced obese rats. Rats (649 +/- 10 g body wt, 27 +/- 1% body fat), with intraperitoneal catheters tethered to infusion swivels, had free access to a 45% fat diet. Food intake, body weight, and adiposity during the 7-wk test period were relatively stable in the vehicle-treated rats (n = 16). None of 10 sCT dosing regimens administered in succession to a second group of rats (n = 18) produced a sustained 25-35% reduction in daily food intake for >5 days, although body weight and adiposity were reduced by 9% (587 +/- 12 vs. 651 +/- 14 g) and 22% (20.6 +/- 1.2 vs. 26.5 +/- 1.1%), respectively, across the 7-wk period. The declining inhibitory effect of sCT on daily food intake with the 6-h interinfusion interval appeared to be due in part to an increase in food intake between infusions. The declining inhibitory effect of sCT on daily food intake with the 2- to 3-h interinfusion interval suggested possible receptor downregulation and tolerance to frequent sCT administration; however, food intake increased dramatically when sCT was discontinued for 1 day after apparent loss of treatment efficacy. Together, these results demonstrate the activation of a potent homeostatic response to increase food intake when sCT reduces food intake and energy reserves in diet-induced obese rats.