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We recently showed that male rats exhibit lower hypophagia and body weight loss compared to female rats following central leptin delivery, suggesting a role for oestradiol in leptin responsiveness. Accordingly, we delivered Ob (leptin) or GFP (control) gene into the brain of male rats that were simultaneously treated with oestradiol or vehicle. In a reciprocal approach, we compared oestradiol-deficient (OVX) with intact females (sham) that received leptin or control vector. Changes in food intake), body weight and body composition were examined. In males, oestradiol and leptin resulted in lower cumulative food intake (15%) and endpoint body weight (5%), although rats receiving dual treatment (oestradiol-leptin) ate 28% less and weighed 22% less than vehicle-control. Changes in food intake were unique to each treatment, with a rapid decrease in vehicle-leptin followed by gradual renormalisation. By contrast, hypophagia in oestradiol-control was of lower amplitude and sporadic. Leptin selectively targeted fat mass and endpoint abdominal fat mass was 65%-80% lower compared to their respective control groups. In females, both leptin groups had lower body weight (endpoint values 20% lower than control groups) with the highest extent in sham animals (endpoint value was 28% less in sham-leptin than in sham-control). OVX rats rapidly started regaining their lost body weight reminiscent of the pattern in males. Leptin rapidly and robustly reduced fat mass with endpoint values 30%-35% less than control treated animals. It appears that leptin and oestradiol decreased food intake and body weight via different mechanisms, with the pattern of oestradiol-leptin being reminiscent of that observed in females and the pattern of OVX-leptin reminiscent of that observed in males. Oestrogen status did not influence initial fat mass loss by leptin. It can be concluded that oestradiol modulates the long-term response to central leptin overexpression, although its actions on energy homeostasis are additive and independent of those of leptin., (© 2018 British Society for Neuroendocrinology.)

The obesity epidemic is multi-generational and is particularly debilitating in the aging population, necessitating the use of pharmaceutical interventions. Recent evidence suggests that increasing the activity of the angiotensin converting enzyme-2 [ACE2]/angiotensin-(1-7)[Ang-(1-7)]/Mas receptor (MasR) axis in obese animal models leads to significant reductions in body weight. It was hypothesized that activation of ACE2 via diminazene aceturate (DIZE) will significantly reduce body weight of rats fed a high fat diet. Young and old (4 and 23 months, respectively) male Fisher 344 × Brown Norway rats were fed 60% high fat diet for one week, and subsequently given either 15 mg/kg/day DIZE s.c. or vehicle for three weeks. DIZE treatment resulted in a significant reduction of food intake and body weight in both young and old animals. However, that decrease was so dramatic in the older animals that they all nearly stopped eating. Interestingly, the TD-NMR assessments revealed that the weight-loss was primarily a result of decreased body fat percentage, with a relative preservation of lean mass. Tissue weights confirm the significant loss of white adipose tissue (WAT), with no change in muscle weights. Gene expression and serum ACE2 activity analyses implied that increased activation of the ACE2/Ang-(1-7)/MasR axis plays a role in reducing fat mass. Collectively, our results suggest that DIZE may be a useful tool in the study of obesity; however, caution is recommended when using this compound in older animals due to severe anorectic effects, although there is a mechanism by which muscle is preserved., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Reducing body weight has been shown to lower blood pressure in obesity-related hypertension. However, success of those lifestyle interventions is limited due to poor long-term compliance. Emerging evidence indicates that feeding schedule plays a role on the regulation of blood pressure. With two studies, we examined the role of feeding schedule on energy homeostasis and blood pressure. In study 1, rats were fed a high-fat diet (HFD) ad libitum for 24 h (Control) or for 12 h during the dark phase (time-restricted feeding, TRF). In study 2, rats fed a HFD were administered a long-acting α-MSH analog at either light onset [melanotan II (MTII) light] or dark onset (MTII dark) or saline (Control). MTII light animals ate most of their calories during the active phase, similar to the TRF group. In study 1, Control and TRF rats consumed the same amount of food and gained the same amount of weight and fat mass. Interestingly, systolic and mean arterial pressure (MAP) was lower in the TRF group. In study 2, food intake was significantly lower in both MTII groups relative to Control. Although timing of injection affected light versus dark phase food consumption, neither body weight nor fat mass differed between MTII groups. Consistent with study 1, rats consuming their calories during the active phase displayed lower MAP. These data indicate that limiting feeding to the active phase reduces blood pressure without the necessity of reducing calories or fat mass, which could be relevant to obesity-related hypertension.

Background & Aim: Overpressure blast-wave induced brain injury (OBI) and its long-term neurological outcome pose significant concerns for military personnel. Our aim is to investigate the mechanism of injury due to OBI., Methods: Rats were divided into 3 groups: (1) Control, (2) OBI (exposed 30psi peak pressure, 2-2.5ms), (3) Repeated OBI (r-OBI) (three exposures over one-week period). Lung and brain (cortex and cerebellum) tissues were collected at 24h post injury., Results: The neurological examination score was worse in OBI and r-OBI (4.2±0.6 and 3.7±0.5, respectively) versus controls (0.7±0.2). A significant positive correlation between lung and brain edema was found. Malondialdehyde (index for lipid peroxidation), significantly increased in OBI and r-OBI groups in cortex (p<0.05) and cerebellum (p<0.01-0.001). The glutathione (endogenous antioxidant) level decreased in cortex (p<0.01) and cerebellum (p<0.05) of r-OBI group when compared with the controls. Myeloperoxidase activity indicating neutrophil infiltration, was significantly (p<0.01-0.05) elevated in r-OBI. Additionally, tissue thromboplastin activity, a coagulation marker, was elevated, indicating a tendency to bleed. NGF and NF-κB proteins along with Iba-1 and GFAP immunoreactivity significantly augmented in the frontal cortex demonstrating microglial activation. Serum biomarkers of injury, NSE, TNF-alpha and leptin, were also elevated., Conclusion: OBI triggers both inflammation and oxidative injury in the brain. This data in conjunction with our previous observations suggests that OBI triggers a cascade of events beginning with impaired cerebral vascular function leading to ischemia and chronic neurological consequences., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Recent evidence indicate that melanotan II (MTII) reduces body mass independently of caloric reduction. Because MTII induces a transient hypophagia, caloric reduction is still considered a primary mechanism for MTII-mediated body mass loss. To examine the contribution of caloric reduction to long-term body mass loss in response to MTII, we centrally infused MTII or vehicle in ad libitum fed (MTII and Control) animals in comparison with a group of animals that were pair-fed (PF) to the MTII group. Food intake and body mass were recorded daily, and body composition was assessed biweekly. The present study demonstrates that central MTII-mediated body mass loss is only partially mediated by caloric restriction, and the long-term body mass loss is independent of the initial hypophagia. More importantly, central MTII administration induced a rapid but sustained fat mass loss, independently of caloric reduction. MTII-treated animals preserved their lean/fat mass ratio throughout the study, whereas PF animals underwent a transient reduction of lean/fat mass ratio that was only normalized when food intake returned to Control level. In summary, it can be concluded that activation of the central melanocortin system in rats persistently reduces body and fat mass independently of caloric reduction.

We evaluated the contribution of brown adipose tissue (BAT) sympathetic innervation on central leptin-mediated weight loss. In a short- and long-term study, F344BN rats were submitted to either a denervation of interscapular BAT (Denervated) or a sham operation (Sham). Animals from each group received the Ob (Leptin) or green fluorescent protein (GFP; Control) gene through a single injection of recombinant adeno-associated virus delivered centrally. Changes in body weight were recorded for 14 or 35 days, after which adipose tissues and skeletal muscles were weighed. In both studies, hypothalamic phosphorylated STAT3 (P-STAT3) was significantly higher in Sham-Leptin and Denervated-Leptin groups compared with their respective Control groups ( P < 0.01), indicating that leptin signaling was enhanced at the end point. We measured uncoupling protein 1 (UCP1), a marker of BAT thermogenic activity, and found a significant induction in Leptin in Sham animals ( P < 0.001) but not in Denervated animals, demonstrating that BAT UCP1 protein was only induced in Sham rats. Both Sham-Leptin and Denervated-Leptin rats lost ~15% of their initial body weight ( P < 0.001) by day 14 and reached a maximum of 18% body weight loss that stabilized over week 3 of treatment, indicating that sympathetic outflow to BAT is not required for leptin-mediated weight loss. In summary, interscapular BAT (iBAT) denervation did not prevent body weight loss following central leptin gene delivery. The present data show that sympathetic innervation of iBAT is not essential for leptin-induced body weight loss.

Brains of females are more sensitive to the acute catabolic actions of leptin. However, sex differences in the long-term physiological responses to central leptin receptor modulation are unknown. Accordingly, we centrally delivered a viral vector to overexpress leptin (Leptin), a neutral leptin receptor antagonist (Leptin-Antagonist) or a green fluorescence protein (GFP) (Control). We examined chronic changes in body weight and composition in male and female rats. Females displayed greater and sustained responses to Leptin, whereas males rapidly lost physiological effects and developed leptin resistance as confirmed by lower acute leptin-mediated phosphorylation of signal transducer and activator of transcription 3 (P-STAT3). Surprisingly, despite persistent physiological responses, Leptin-females also exhibited reduced acute leptin-mediated P-STAT3, suggesting an onset of leptin resistance near time of death. In line with this interpretation, Leptin-females and Control-females consumed the same amount of food on the last day of the experiment. Both Leptin-Antagonist groups gained similar percentages of their initial body weight and fat mass, whereas only Leptin-Antagonist-females gained lean body mass. Consequently, the lean/fat mass ratio with Leptin-Antagonist was preserved in females and decreased in males, suggesting a deterioration of body composition in males. In summary, the present study establishes that females are more responsive to long-term central leptin overexpression than males and that leptin antagonism has a greater physiological impact in males. The hormone environment may have played a role in these processes; however, future studies are needed to establish whether such physiological responses are mediated by female or male sex hormones., (© 2017 British Society for Neuroendocrinology.)

Prenatal overnutrition affects development into adulthood and influences risk of obesity. We assessed the transgenerational effect of maternal Western diet (WD) consumption on offspring physical activity. Voluntary wheel running was increased in juvenile (4-7 wk of age), but decreased in adult (16-19 wk of age), F 1 female WD offspring In contrast, no wheel-running differences in F 1 male offspring were observed. Increased wheel running in juvenile female WD offspring was associated with up-regulated dopamine receptor (DRD)-1 and -2 in the nucleus accumbens (NAc) and with down-regulated Lepr in the ventral tegmental area (VTA). Conversely, decreased wheel running by adult female WD offspring was associated with down-regulated DRD1 in the NAc and with up-regulated Lepr in the VTA. Body fat, leptin, and insulin were increased in male, but not in female, F 1 WD offspring. Recombinant virus (rAAV) leptin antagonism in the VTA decreased wheel running in standard diet but not in WD F 1 female offspring. Analysis of F 2 offspring found no differences in wheel running or adiposity in male or female offspring, suggesting that changes in the F 1 generation were related to in utero somatic reprogramming. Our findings indicate prenatal WD exposure leads to age-specific changes in voluntary physical activity in female offspring that are differentially influenced by VTA leptin antagonism.-Ruegsegger, G. N., Grigsby, K. B., Kelty, T. J., Zidon, T. M., Childs, T. E., Vieira-Potter, V. J., Klinkebiel, D. L., Matheny, M., Scarpace, P. J., Booth, F. W. Maternal Western diet age-specifically alters female offspring voluntary physical activity and dopamine- and leptin-related gene expression., (© FASEB.)

Melanotan II (MTII) is a potent appetite suppressor that rapidly reduces body mass. Given the rapid loss of anorexic response upon chronic MTII treatment, most investigations have focused on the initial physiological adaptations. However, other evidence supports MTII as a long-term modulator of energy balance that remains to be established. Therefore, we examined the chronic effects of MTII on energy homeostasis. MTII (high or low dose) or artificial cerebrospinal fluid (aCSF) was infused into the lateral ventricle of the brain of 6-month-old F344BN rats (6-7/group) over 40 days. MTII suppressed appetite in a dose-dependent manner (P < 0.05). Although food intake promptly rose back to control level, body mass was persistently reduced in both MTII groups (P < 0.01). At day 40, both MTII groups displayed lower adiposity than the aCSF animals (P < 0.01). These results show that MTII chronically reduces body mass without the requirement of long-term caloric restriction. Our study proposes that food restriction helps initiate mass loss; however, combined with a secondary pharmacological approach preserving a negative energy balance state over time may help combat obesity.

Aim: The aim of this study was to investigate the effect of a high salt (HS) diet on age-related changes in blood pressure (BP) and the possible role played by regulatory central mechanisms., Methods: Young (5 months) and old (27 months) male Fischer 344 × Brown Norway (F344/BN) rats were fed standard chow or 8% HS diet for 12 days. BP and heart rate (HR) were measured by telemetry., Results: Mean arterial BP (MAP) was significantly elevated in old rats during the day and night when compared with young animals. The HS diet further elevated MAP in both age groups, and the increase was more pronounced in the old animals, while HR was not altered by age or HS diet. In addition, cardiovascular responses to restraint stress were diminished in the old when compared with the young and were unchanged with HS diet in either age group. Both age and the HS diet elevated the adrenomedullary mRNA levels of tyrosine hydroxylase, an indicator for sympathoexcitation. HS diet enhanced intracerebroventricular angiotensin II (AngII)-induced BP and HR elevations in both age groups. AngII type 1 receptor mRNA increased significantly in the hypothalamus with age and HS diet. Furthermore, hypothalamic p22phox mRNA and gp91phox protein, subunits of NADPH oxidase, as well as NADPH oxidase activity increased with the HS diet in the old animals, whereas antioxidant enzymes that decreased with age yet remained unaltered with the HS diet., Conclusion: Our findings indicate that sensitivity of BP to HS diet increases with age, and that central AngII-induced pressor responses are diminished in old rats compared with the young both under control conditions and during HS diet treatment. These changes are paralleled by increases in the expression and NADPH oxidase activity in the hypothalamus, possibly leading to central oxidative stress-mediated sympathoexcitation and high BP., (© 2017 S. Karger AG, Basel.)

Hypothalamic inflammation and increased oxidative stress are believed to be mechanisms that contribute to obesity. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol), a free radical scavenger, has been shown to reduce inflammation and oxidative stress. We hypothesized that brain infusion of tempol would reduce oxidative stress, and thus would reduce food intake and body weight and improve body composition in rats with age-related obesity and known elevated oxidative stress. Furthermore, we predicted an associated increase in markers of leptin signalling, including the silent mating type information regulator 2 homolog 1 (SIRT1)/5'AMP-activated protein kinase (AMPK) pathway and the signal transducer and activator of transcription 3 (STAT3) pathway. For this purpose, osmotic minipumps were placed in the intracerebroventricular region of young (3 months) and aged (23 months) male Fischer 344 x Brown Norway rats for the continuous infusion of tempol or vehicle for 2 weeks. Tempol significantly decreased (p < 0.01) nicotinamide adenine dinucleotide phosphate oxidase activity in the hypothalamus but failed to reduce food intake or weight gain and did not alter body composition. SIRT1 activity and Acetyl p53 were decreased and phosphorylation of AMPK was increased with age, but they were unchanged with tempol. Basal phosphorylation of STAT3 was unchanged with age or tempol. These results indicate that tempol decreases oxidative stress but fails to alter feeding behaviour, body weight, or body composition. Moreover, tempol does not modulate the SIRT1/AMPK/p53 pathway and does not change leptin signalling. Thus, a reduction in hypothalamic oxidative stress is not sufficient to reverse age-related obesity.

The authors have previously demonstrated that a low and intermittent peripheral dose of rapamycin (1 mg/kg three times/week) to rats inhibited mTORC1 signalling, but avoided the hyperlipidemia and diabetes-like syndrome associated with higher doses of rapamycin. The dosing regimen reduced food intake, body weight, adiposity, serum leptin and triglycerides. mTORC1 signalling was inhibited in both liver and hypothalamus, suggesting some of the actions, in particular the decrease in food intake, may be the results of a central mechanism. To test this hypothesis, rapamycin (30 μg/day for 4 weeks) was infused into 23-25-month-old F344xBN rats by intracerebroventricular (icv) mini pumps. Our results demonstrated that central infusion did not alter food intake or body weight, although there was a tendency for a decrease in body weight towards the end of the study. mTORC1 signalling, evidenced by decreased phosphorylation of S6 protein at end of 4 weeks, was not activated in liver, hypothalamus or hindbrain. Fat and lean mass, sum of white adipose tissues, brown adipose tissue, serum glucose, insulin and leptin levels remained unchanged. Thus, these data suggest that the anorexic and body weight responses evident with peripheral rapamycin are not the result of direct central action. The tendency for decreased body weight towards the end of study, suggests that there is either a slow transport of centrally administered rapamycin into the periphery, or that there is delayed action of rapamycin at sites in the brain., (© 2016 John Wiley & Sons Australia, Ltd.)

This investigation examines whether a low intermittent dose of rapamycin will avoid the hyperlipidemia and diabetes-like syndrome associated with rapamycin while still decreasing body weight and adiposity in aged obese rats. Furthermore, we examined if the rapamycin-mediated decrease in serum leptin was a reflection of decreased adiposity, diminished leptin synthesis, or both. To these ends, rapamycin (1mg/kg) was administered three times a week to 3 and 24-month old rats. Body weight, food intake, body composition, mTORC1 signaling, markers of metabolism, as well as serum leptin levels and leptin synthesis in adipose tissue were examined and compared to that following a central infusion of rapamycin. Our data suggest that the dosing schedule of rapamycin acts on peripheral targets to inhibit mTORC1 signaling, preferentially reducing adiposity and sparing lean mass in an aged model of obesity resulting in favorable outcomes on blood triglycerides, increasing lean/fat ratio, and normalizing elevated serum leptin with age. The initial mechanism underlying the rapamycin responses appears to have a peripheral action and not central. The peripheral rapamycin responses may communicate an excessive nutrients signal to the hypothalamus that triggers an anorexic response to reduce food consumption. This coupled with potential peripheral mechanism serves to decrease adiposity and synthesis of leptin., (© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Rapamycin, an inhibitor of the mammalian target of rapamycin pathway, has been shown to increase mammalian life span; less is known concerning its effect on healthspan. The primary aim of this study was to examine rapamycin's role in the alteration of several physiological and behavioral outcomes compared with the healthspan-inducing effects of intermittent feeding (IF), another life-span-enhancing intervention. Male Fisher 344 × Brown Norway rats (6 and 25 months of age) were treated with rapamycin or IF for 5 weeks. IF and rapamycin reduced food consumption and body weight. Rapamycin increased relative lean mass and decreased fat mass. IF failed to alter fat mass but lowered relative lean mass. Behaviorally, rapamycin resulted in high activity levels in old animals, IF increased levels of "anxiety" for both ages, and grip strength was not significantly altered by either treatment. Rapamycin, not IF, decreased circulating leptin in older animals to the level of young animals. Glucose levels were unchanged with age or treatment. Hypothalamic AMPK and pAMPK levels decreased in both older treated groups. This pattern of results suggests that rapamycin has more selective and healthspan-inducing effects when initiated late in life., (© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Leptin administration results in leptin resistance presenting a significant barrier to therapeutic use of leptin. Consequently, we examined two hypotheses. The first examined the relationship between leptin dose and development of physiological and biochemical signs of leptin resistance. We hypothesized lower doses of leptin would produce proportional reductions in body weight without the adverse leptin-induced leptin resistance. The second compared pulsed central leptin infusion to continuous leptin infusion. We hypothesized that pulsed infusion at specific times of the day would evoke favorable body weight reductions while tempering the development of leptin-induced leptin resistance. The first experiment examined leptin responsiveness, including food intake, body weight and hypothalamic STAT3 phosphorylation to increasing doses of viral gene delivery of leptin. Varying the dose proved inconsequential with respect to long-term therapy and demonstrated proportional development of leptin resistance. The second experiment examined leptin responsiveness to pulsed central leptin infusion, comparing pulsed versus constant infusion of 3μg/day leptin or a 2h morning versus a 2h evening pulsed leptin infusion. Pulsed delivery of the supramaximal dose of 3μg/day was not different than constant delivery. Morning pulsed infusion of the submaximal dose of 0.25μg reduces food intake only over subsequent immediate meal period and was associated with body weight reductions, but results in cellular leptin resistance. Evening pulsed infusion did not decrease food intake but reduces body weight and maintains full leptin signaling. The positive benefit for pulsed delivery remains speculative, yet potentially may provide an alternative mode of leptin therapy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Resveratrol, a polyphenol phytoalexine, has been shown to play a neuroprotective role in the neurodegenerative process in Alzheimer's disease (AD) and improve memory function in dementia. However, the in vivo effect of resveratrol in normal aging models of learning and memory has not yet been evaluated. Therefore, the present neurobehavioral study was undertaken to evaluate the effect of resveratrol on cognitive impairment induced by aging in passive avoidance and Morris water maze (MWM) tests. Male Wistar albino rats were divided into four groups: young control (4month), young resveratrol (4month+RESV), old control (24month) and old resveratrol (24month+RESV). Resveratrol (50mg/kg/day) was given to the 4month+RESV and 24month+RESV groups orally for 12weeks. There was no significant difference between the groups for the first day of latency, while in aged rats, the second day of latency was significantly shortened compared to the young group in the passive avoidance test (p<0.05). Additionally, in the MWM test, the results showed a decrease in the time spent in the escape platform's quadrant in the probe test in aged rats (p<0.05). The administration of resveratrol at 50mg/kg/day increased the retention scores in the passive avoidance test and the time spent in the escape platform's quadrant in the MWM task (p<0.05). Furthermore resveratrol attenuated the protein levels of TNFα and IL1β in the 24-month group. These findings indicate that aging impairs emotional and spatial learning-memory and resveratrol reverses the effect of age-related learning and memory impairment. The results of this study suggest that resveratrol is effective in preventing cognitive deficit in aged rats by inhibiting the production of inflammatory cytokines., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The objective of the study was to determine the effects of a high fat (HF) diet alone or with high fructose (HF/F) on functional and structural changes in the basilar arteries and cardiovascular health parameters in rats. Male Sprague Dawley rats were fed either a HF (30%) or HF/F (30/40%) diet for 12 weeks. The basilar artery was cannulated in a pressurized system (90 cm H2O) and vascular responses to KCl (30 - 120 mM), endothelin (10(-11) - 10(-7) M), acetylcholine (ACh) (10(-10) - 10(-4) M), diethylamine (DEA)-NONO-ate (10(-10) - 10(-4) M), and papaverine (10(-10) - 10(-4) M) were evaluated. Rats were also monitored for food intake, body weight, blood lipids, blood pressure, and heart rate. At death, asymmetrical dimethyl arginine level (ADMA) and leptin were assayed in serum. Although there was no significant difference in weight gain and food intake, HF and HF/F diets increased body fat composition and decreased the lean mass. HF/F diet accelerated the development of dyslipidemia. Although resting blood pressure remained unchanged, stress caused a significant elevation in blood pressure and a modest increase in heart rate in HF fed rats. Both HF and HF/F diet resulted in decreased response to endothelium-dependent and -independent relaxation, whereas increased basilar artery wall thickness was observed only in HF group. Serum leptin levels positively correlated with wall thickness. Moreover serum ADMA was increased and eNOS immunofluorescence was significantly decreased with both diets. These data suggest that the presence of high fructose in a HF diet does not exacerbate the detrimental consequences of a HF diet on basilar artery function.

Dietary-induced obesity (DIO) resulting from high-fat (HF) or high-sugar diets produces a host of deleterious metabolic consequences including adverse bone development. We compared the effects of feeding standard rodent chow (Control), a 30% moderately HF (starch-based/sugar-free) diet, or a combined 30%/40% HF/high-fructose (HF/F) diet for 12weeks on cancellous/cortical bone development in male Sprague-Dawley rats aged 8weeks. Both HF feeding regimens reduced the lean/fat mass ratio, elevated circulating leptin, and reduced serum total antioxidant capacity (tAOC) when compared with Controls. Distal femur cancellous bone mineral density (BMD) was 23-34% lower in both HF groups (p<0.001) and was characterized by lower cancellous bone volume (BV/TV, p<0.01), lower trabecular number (Tb.N, p<0.001), and increased trabecular separation versus Controls (p<0.001). Cancellous BMD, BV/TV, and Tb.N were negatively associated with leptin and positively associated with tAOC at the distal femur. Similar cancellous bone deficits were observed at the proximal tibia, along with increased bone marrow adipocyte density (p<0.05), which was negatively associated with BV/TV and Tb.N. HF/F animals also exhibited lower osteoblast surface and reduced circulating osteocalcin (p<0.05). Cortical thickness (p<0.01) and tissue mineral density (p<0.05) were higher in both HF-fed groups versus Controls, while whole bone biomechanical characteristics were not different among groups. These results demonstrate that "westernized" HF diets worsen cancellous, but not cortical, bone parameters in skeletally-immature male rats and that fructose incorporation into HF diets does not exacerbate bone loss. In addition, they suggest that leptin and/or oxidative stress may influence DIO-induced alterations in adolescent bone development., (Published by Elsevier Inc.)

Purpose: To determine whether resveratrol improves the adverse effects age on vascular function in mesenteric arteries (MAs), and diminishes the hyperactivity in adrenal gland with age., Methods: Male F344 x Brown Norway rats were assigned to 6-month control (YC), 6-month resveratrol (YR), 24-month control (OC) and 24-month resveratrol (OR). Resveratrol (15 mg/kg) was provided to resveratrol groups in drinking water for 14 days., Results: Concentration response curves to phenylephrine (PE, 10(-9)-10(-5)M), acetylcholine (Ach, 10(-9)-10(-5)M) and resveratrol (10(-8)-10(-4)M) were evaluated in pressurized isolated MAs. The Ach concentration-response curve was right shifted with maximal response diminished in OC compared with YC rats. These effects were reversed by resveratrol treatment. The resveratrol-mediated relaxant responses were unchanged with age or resveratrol suggesting an endothelium-independent mechanism. Resveratrol tended to increase endothelial nitric oxide synthase; caused no effect on copper-zinc superoxide dismutase; and normalized the age-related elevatation in DβH and NPY levels in adrenal medulla, two indicators of sympathetic activity., Conclusion: These data indicate that resveratrol reverses age-related dysfunction in endothelium-dependent vasodilation in MAs and partially reverses hyperactivity of adrenomedullary function with age. This treatment may have a therapeuticpotential in the treatment of cardiovascular diseases or hypertension in the elderly.

Overpressure blast-wave induced brain injury (OBI) leads to progressive pathophysiologic changes resulting in a reduction in brain blood flow, blood brain barrier breakdown, edema, and cerebral ischemia. The aim of this study was to evaluate cerebral vascular function after single and repeated OBI. Male Sprague-Dawley rats were divided into three groups: Control (Naive), single OBI (30 psi peak pressure, 1 to 2 msec duration), and repeated (days 1, 4, and 7) OBI (r-OBI). Rats were killed 24 hours after injury and the basilar artery was isolated, cannulated, and pressurized (90 cm H2O). Vascular responses to potassium chloride (KCl) (30 to 100 mmol/L), endothelin-1 (10(-12) to 10(-7) mol/L), acetylcholine (ACh) (10(-10) to 10(-4) mol/L) and diethylamine-NONO-ate (DEA-NONO-ate) (10(-10) to 10(-4) mol/L) were evaluated. The OBI resulted in an increase in the contractile responses to endothelin and a decrease in the relaxant responses to ACh in both single and r-OBI groups. However, impaired DEA-NONO-ate-induced vasodilation and increased wall thickness to lumen ratio were observed only in the r-OBI group. The endothelin-1 type A (ET(A)) receptor and endothelial nitric oxide synthase (eNOS) immunoreactivity were significantly enhanced by OBI. These findings indicate that both single and r-OBI impairs cerebral vascular endothelium-dependent dilation, potentially a consequence of endothelial dysfunction and/or vascular remodelling in basilar arteries after OBI.

The concept of 'successful aging' has long intrigued the scientific community. Despite this long-standing interest, a consensus definition has proven to be a difficult task, due to the inherent challenge involved in defining such a complex, multi-dimensional phenomenon. The lack of a clear set of defining characteristics for the construct of successful aging has made comparison of findings across studies difficult and has limited advances in aging research. A consensus on markers of successful aging is furthest developed is the domain of physical functioning. For example, walking speed appears to be an excellent surrogate marker of overall health and predicts the maintenance of physical independence, a cornerstone of successful aging. The purpose of the present article is to provide an overview and discussion of specific health conditions, behavioral factors, and biological mechanisms that mark declining mobility and physical function and promising interventions to counter these effects. With life expectancy continuing to increase in the United States and developed countries throughout the world, there is an increasing public health focus on the maintenance of physical independence among all older adults., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The present investigation examined whether leptin stimulation of ventral tegmental area (VTA) or nucleus of the solitary tract (NTS) has a role in body weight homeostasis independent of the medial basal hypothalamus (MBH). To this end, recombinant adeno-associated viral techniques were employed to target leptin overexpression or overexpression of a dominant negative leptin mutant (leptin antagonist). Leptin antagonist overexpression in MBH or VTA increased food intake and body weight to similar extents over 14 days in rats. Simultaneous overexpression of leptin in VTA with antagonist in MBH resulted in food intake and body weight gain that were less than with control treatment but greater than with leptin alone in VTA. Notably, leptin overexpression in VTA increased P-STAT3 in MBH along with VTA, and leptin antagonist overexpression in the VTA partially attenuated P-STAT3 levels in MBH. Interestingly, leptin antagonist overexpression elevated body weight gain, but leptin overexpression in the NTS failed to modulate either food intake or body weight despite increased P-STAT3. These data suggest that leptin function in the VTA participates in the chronic regulation of food consumption and body weight in response to stimulation or blockade of VTA leptin receptors. Moreover, one component of VTA-leptin action appears to be independent of the MBH, and another component appears to be related to leptin receptor-mediated P-STAT3 activation in the MBH. Finally, leptin receptors in the NTS are necessary for normal energy homeostasis, but mostly they appear to have a permissive role. Direct leptin activation of NTS slightly increases UCP1 levels, but has little effect on food consumption or body weight., (© 2014 Society for Endocrinology.)

Cancer progression is associated with inflammation, increased metabolic demand, infection, cachexia, and eventually death. Myeloid-derived suppressor cells (MDSCs) commonly expand during cancer and are associated with adaptive immune suppression and inflammatory metabolite production. We propose that cancer-induced cachexia is driven at least in part by the expansion of MDSCs. MDSC expansion in 4T1 mammary carcinoma-bearing hosts is associated with induction of a hepatic acute-phase protein response and altered host energy and fat metabolism, and eventually reduced survival to polymicrobial sepsis and endotoxemia. Similar results are also seen in mice bearing a Lewis lung carcinoma and a C26 colon adenocarcinoma. However, a similar cachexia response is not seen with equivalent growth of the 66C4 subclone of 4T1, in which MDSC expansion does not occur. Importantly, reducing MDSC numbers in 4T1-bearing animals can ameliorate some of these late responses and reduce susceptibility to inflammation-induced organ injury and death. In addition, administering MDSCs from both tumor- and nontumor-bearing mice can produce an acute-phase response. Thus, we propose a previously undescribed mechanism for the development of cancer cachexia, whereby progressive MDSC expansion contributes to changes in host protein and energy metabolism and reduced resistance to infection., (Copyright © 2014 by The American Association of Immunologists, Inc.)

Aging leads to progressive pathophysiological changes in blood vessels of the brain and periphery. The aim of this study was to evaluate the effects of aging on cerebral vascular function and structure. Basilar arteries were isolated from male Fischer 344 cross Brown Norway (F344xBN) rats at 3, 8, and 24 months of age. The basilar arteries were cannulated in the pressurized system (90 cm H2O). Contractile responses to KCl (30-120 mmol/L) and endothelin-1 (10(-11)-10(-7) mol/L) were evaluated. Responses to acetylcholine (ACh) (10(-10)-10(-4) mol/L), diethylamine (DEA)-NONO-ate (10(-10)-10(-4) mol/L), and papaverin (10(-10)-10(-4) mol/L) were assessed to determine both endothelium-dependent and endothelium-independent responsiveness. Advanced aging (24 months) decreased responses of the basilar artery to both the contractile and relaxing agents; whereas, DEA-induced dilation was significantly higher in the 8-month-old group compared with the younger and older groups. The arterial wall-to-lumen ratio was significantly increased in 24-month-old rats. Smooth muscle cell count was also decreased in old rats. These findings indicate that aging produces dysfunction of both the endothelium and the vascular smooth muscle in the basilar artery. Aging also alters wall structure of the basilar artery, possibly through decreases in smooth muscle cell number and concomitant hypertrophy., (© 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Background: Mechanical ventilation (MV) is a method of maintaining appropriate gas exchange in patients who are unable to sustain adequate alveolar ventilation. While lifesaving in the short-term, prolonged MV leads to altered cardiovascular responses and enhanced lung injury, but the exact mechanism is unknown. Therefore, we investigated the involvement of the sympathoadrenergic and renin-angiotensin system in MV-induced altered cardiovascular responses., Methods: Sprague-Dawley rats were divided into six groups: (1) spontaneous breathing (SB); (2) SB + enalapril (100 μg/kg intravenous infusion); (3) SB + losartan (100 μg/kg infusion); (4) 12 h of MV; (5) MV + enalapril; and (6) MV + losartan. After the animals were sacrificed, blood and tissue samples were collected. Tyrosine hydroxylase, dopamine beta hydroxylase, and neuropeptide Y were measured in adrenal medulla and hypothalamus, whereas AT1 was measured in lung tissues by Western blot. Norepinephrine enzyme-linked immunosorbent assay and total antioxidant capacity were assayed in plasma., Results: Our findings indicated that MV increases the sympathetic activation markers in adrenal medulla and hypothalamus. Moreover, oxidative stress was increased in lung and brain tissues. Treatment with enalapril or losartan reduced the lipid peroxidation in lung and brain tissues, while preserving the tissue glutathione content and plasma antioxidant capacity., Conclusions: These data demonstrate that the inhibition of the renin-angiotensin system by enalapril or losartan may reduce the MV-induced increase in sympathetic activity markers and oxidative stress, and thus, may have a beneficial effect as adjuvant therapy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Explosive overpressure brain injury (OBI) impacts the lives of both military and civilian population. We hypothesize that a single exposure to OBI results in increased hypothalamic expression of oxidative stress and activation of the sympatho-adrenal medullary axis. Since a key component of blast-induced organ injury is the primary overpressure wave, we assessed selective biochemical markers of autonomic function and oxidative stress in male Sprague Dawley rats subjected to head-directed overpressure insult. Rats were subjected to single head-directed OBI with a 358kPa peak overpressure at the target. Control rats were exposed to just noise signal being placed at ~2m distance from the shock tube nozzle. Sympathetic nervous system activation of the adrenal medullae (AM) was evaluated at 6h following blast injury by assessing the expression of catecholamine biosynthesizing enzymes, tyrosine hydroxylase (TH), dopamine-β hydroxylase (DβH), neuropeptide Y (NPY) along with plasma norepinephrine (NE). TH, DβH and NPY expression increased 20%, 25%, and 91% respectively, following OBI (P<0.05). Plasma NE was also significantly elevated by 23% (P<0.05) following OBI. OBI significantly elevated TH (49%, P<0.05) in the nucleus tractus solitarius (NTS) of the brain stem while AT1 receptor expression and NADPH oxidase activity, a marker of oxidative stress, was elevated in the hypothalamus following OBI. Collectively, the increased levels of TH, DβH and NPY expression in the rat AM, elevated TH in NTS along with increased plasma NE suggest that single OBI exposure results in increased sympathoexcitation. The mechanism may involve the elevated AT1 receptor expression and NADPH oxidase levels in the hypothalamus. Taken together, such effects may be important factors contributing to pathology of brain injury and autonomic dysfunction associated with the clinical profile of patients following OBI., (Published by Elsevier Ireland Ltd.)

Classically, leptin resistance has been associated with increased body fat and circulating leptin levels, and the condition is believed to contribute to the onset and/or maintenance of obesity. Although a great deal is known about the central nervous system mechanisms mediating leptin resistance, considerably less is known about the role of diet in establishing and maintaining this altered hormonal state. An exciting new finding has recently been published demonstrating the existence of leptin resistance in normal-weight rats with lean leptin levels by feeding them a high-concentration-fructose diet. This finding has opened the possibility that specific macronutrients may be capable of inducing leptin resistance, independently of the amount of body fat or circulating leptin present in the treated animals. This review describes several lines of research that have recently emerged indicating that specific types of dietary sugars and fats are capable of inducing leptin resistance in experimental rodent models. The results further show that diet-induced leptin resistance is capable of increasing energy intake and elevating body weight gain under appropriate dietary challenges. It appears that biological mechanisms on multiple levels may underlie the dietary induction of leptin resistance, including alterations in the leptin blood-to-brain transport system, in peripheral glucose metabolism, and in central leptin receptor signaling pathways. What is clear from the findings reviewed here is that diet-induced leptin resistance can occur in the absence of elevated circulating leptin levels and body weight, rendering it a potential cause and/or predisposing factor to excess body weight gain and obesity.

High-fat feeding or CNS leptin overexpression in chow-fed rats results in a region-specific cellular leptin resistance in medial basal hypothalamic regions and the ventral tegmental area (VTA). The present investigation examined the effects of targeted chronic leptin overexpression in the VTA as compared with the medial basal hypothalamus on long-term body weight homeostasis. The study also examined if this targeted intervention conserves regional leptin sensitivity or results in localized leptin resistance. Cellular leptin resistance was assessed by leptin-stimulated phosphorylation of signal transducers and activators of transcription 3 (STAT3). Tyrosine hydroxylase was measured in hypothalamus and VTA along with brown adipose tissue uncoupling protein 1. Leptin overexpression in VTA tempered HF-induced obesity, but to a slightly lesser extent than that with leptin overexpression in the hypothalamus. Moreover, the overexpression of leptin in the VTA stimulated cellular STAT3 phosphorylation in several regions of the medial basal hypothalamus, whereas verexpression in the hypothalamus did not activate STAT3 signaling in the VTA. This unidirectional trans-stimulation did not appear to involve migration of either the vector or the gene product. Long-term leptin overexpression in either the medial basal hypothalamus or VTA caused desensitization of leptin signaling in the treated region and cross-desensitization of leptin signaling in the untreated region. These results demonstrate a role of leptin receptors in the VTA in long-term body weight regulation, but the trans-activation of the hypothalamus following VTA leptin stimulation suggests that an integrative response involving both brain regions may account for the observed physiological outcomes., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Voluntary wheel running (WR) is a form of physical activity in rodents that influences ingestive behavior. The present report describes an anorexic behavior triggered by the simultaneous introduction of a novel diet and WR. This study examined the sequential, compared with the simultaneous, introduction of a novel high-fat (HF) diet and voluntary WR in rats of three different ages and revealed a surprising finding; the simultaneous introduction of HF food and voluntary WR induced a behavior in which the animals chose not to eat although food was available at all times. This phenomenon was apparently not due to an aversion to the novel HF diet because introduction of the running wheels plus the HF diet, while continuing the availability of the normal chow diet did not prevent the anorexia. Moreover, the anorexia was prevented with prior exposure to the HF diet. In addition, the anorexia was not related to extent of WR but dependent on the act of WR. The introduction a HF diet and locked running wheels did not induce the anorexia. This voluntary anorexia was accompanied by substantial weight loss, and the anorexia was rapidly reversed by removal of the running wheels. Moreover, the HF/WR-induced anorexia is preserved across the age span despite the intrinsic decrease in WR activity and increased consumption of HF food with advancing age. The described phenomenon provides a new model to investigate anorexia behavior in rodents., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Caloric restriction and physical exercise have proven beneficial against age-associated changes in body composition and declining physical performance; however, little is known regarding what benefit these interventions might have when initiated late in life. The study of mimetics of diet and exercise and the combination thereof may provide additional treatments for a vulnerable elderly population; however, how and when to initiate such interventions requires consideration in developing the most safe and efficacious treatment strategies. In this review, we focus on preclinical late-life intervention studies, which assess the relationship between physical function, sarcopenia, and body composition. We provide a conceptual framework for the ever-changing definition of sarcopenia and a rationale for the use of an appropriate rodent model of this condition. We finish by providing our perspective regarding the implications of this body of work and future areas of research that may also contribute to the ultimate goal of extending healthspan.

The activation of proopiomelanocortin (POMC) neurons in different regions of the brain, including the arcuate nucleus of the hypothalamus (ARC) and the nucleus of the solitary tract curtails feeding and attenuates body weight. In this study, we compared the effects of delivery of a recombinant adeno-associated viral (rAAV) construct encoding POMC to the ARC with delivery to the ventral tegmental area (VTA). F344×Brown Norway rats were high-fat (HF) fed for 14 days after which self-complementary rAAV constructs expressing either green fluorescent protein or the POMC gene were injected using coordinates targeting either the VTA or the ARC. Corresponding increased POMC levels were found at the predicted injection sites and subsequent α-melanocyte-stimulating hormone levels were observed. Food intake and body weight were measured for 4 months. Although caloric intake was unaltered by POMC overexpression, weight gain was tempered with POMC overexpression in either the VTA or the ARC compared with controls. There were parallel decreases in adipose tissue reserves. In addition, levels of oxygen consumption and brown adipose tissue uncoupling protein 1 were significantly elevated with POMC treatment in the VTA. Interestingly, tyrosine hydroxylase levels were increased in both the ARC and VTA with POMC overexpression in either the ARC or the VTA. In conclusion, these data indicate a role for POMC overexpression within the VTA reward center to combat HF-induced obesity.

Chronic consumption of a Western-type diet, containing both elevated sugar and fat, results in leptin resistance. We hypothesised that fructose, as part of the sugar component of Western-type diets, is one causative ingredient in the development of leptin resistance and that removal of this component will prevent leptin resistance despite high fat (HF) content. We fed rats a sugar-free (SF), 30 % HF (SF/HF) diet or a 40 % high-fructose (HFr), 30 % HF (HFr/HF) diet for 134 d. The HFr/HF diet resulted in impaired anorexic and body-weight responses to both peripherally (0·6 mg/kg, assessed on day 65 of the diet) and centrally (1·5 μg/d, assessed on days 129-134) administered leptin, whereas SF/HF-fed rats were fully leptin responsive. At day 70, half the HFr/HF-fed animals were switched to the SF/HF diet, reversing the leptin resistance (assessed 18 d after the diet switch). The HFr/HF diet elevated serum leptin and reduced adiponectin, and levels were restored abruptly at day 3 after switching to the SF/HF diet. These data demonstrate that a diet containing both HFr and fat leads to leptin resistance, while an isoenergetic SF/HF diet does not. Moreover, removal of fructose from this diet reverses the leptin resistance and the elevated leptin, suggesting a cause-and-effect relationship. These data suggest that fructose is the bioactive component of a HF/high-sugar diet that is essential for the induction of leptin resistance.

Aging and obesity both have a significant impact on central blood pressure (BP) regulation, and previous studies indicated that changes in central redox signaling with age may affect high-fat (HF) diet-induced cardiovascular responses. Therefore, we investigated the effects of 60% HF feeding on BP regulation in young adult (5 mo) and old (26 mo) Fischer-344 × Brown-Norway rats. Radiotelemetric transmitters were implanted to measure BP, heart rate (HR), locomotor activity, and spontaneous baroreflex sensitivity. Expression and activity of NADPH oxidase and ANG II type 1 receptor were assessed in the hypothalamus and in the nucleus tractus solitarii. Old animals gained more weight on HF diet compared with young, whereas central NADPH oxidase expression and activity elevated similarly in the two age groups. After an initial hypotensive and tachycardic response during the first week of HF feeding, BP in young animals increased and became significantly elevated after 6 wk of HF feeding. In contrast, BP in old animals remained depressed. Nighttime HR and locomotor activity decreased in both young and old rats fed with HF diet, but these changes were more significant in young rats. As a result, amplitudes of circadian variation of BP, HR, and activity that were originally higher in young rats declined significantly and became similar in the two age groups. In conclusion, our experiments led to the surprising finding that HF diet has a more serious impact on cardiovascular regulation in young animals compared with old.

Pro-opiomelanocortin (POMC) neurons are identified in two brain sites, the arcuate nucleus of the hypothalamus and nucleus of the solitary tract (NTS) in brainstem. Earlier pharmacological and POMC gene transfer studies demonstrate that melanocortin activation in either site alone improves insulin sensitivity and reduces obesity. The present study, for the first time, investigated the long-term efficacy of POMC gene transfer concurrently into both sites in the regulation of energy metabolism in aged F344xBN rats bearing adult-onset obesity. Pair feeding was included to reveal food-independent POMC impact on energy expenditure. We introduced adeno-associated virus encoding either POMC or green fluorescence protein to the two brain areas in 22-month-old rats, then recorded food intake and body weight, assessed oxygen consumption, serum leptin, insulin and glucose, tested voluntary wheel running, analysed POMC expression, and examined fat metabolism in brown and white adipose tissues. POMC mRNA was significantly increased in both the hypothalamus and NTS region at termination. Relative to pair feeding, POMC caused sustained weight reduction and additional fat loss, lowered fasting insulin and glucose, and augmented white fat hormone-sensitive lipase activity and brown fat uncoupling protein 1 level. By wheel running assessment, the POMC animals ran twice the distance as the Control or pair-fed rats. Thus, the dual-site POMC treatment ameliorated adult-onset obesity effectively, involving a moderate hypophagia lasting ∼60 days, enhanced lipolysis and thermogenesis, and increased physical activity in the form of voluntary wheel running. The latter finding provides a clue for countering age-related decline in physical activity., (European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd. No claim to original US government works.)

Diet-induced obesity (DIO) results in region-specific cellular leptin resistance in the arcuate nucleus (ARC) of the hypothalamus in one strain of mice and in several medial basal hypothalamic regions in another. We hypothesized that the ventral tegmental area (VTA) is also likely susceptible to diet-induced and leptin-induced leptin resistance in parallel to that in hypothalamic areas. We examined two forms of leptin resistance in F344xBN rats, that induced by 6-months of high fat (HF) feeding and that induced by 15-months of central leptin overexpression by use of recombinant adeno-associated viral (rAAV)-mediated gene delivery of rat leptin. Cellular leptin resistance was assessed by leptin-stimulated phosphorylation of signal transducers and activators of transcription 3 (STAT3) in medial basal hypothalamic areas and the VTA. The regional pattern and degree of leptin resistance with HF was distinctly different than that with leptin overexpression. Chronic HF feeding induced a cellular leptin resistance that was identified in the ARC and VTA, but absent in the lateral hypothalamus (LH), ventromedial hypothalamus (VMH), and dorsomedial hypothalamus (DMH). In contrast, chronic central leptin overexpression induced cellular leptin resistance in all areas examined. The identification of leptin resistance in the VTA, in addition to the leptin resistance in the hypothalamus, provides one potential mechanism, underlying the increased susceptibility of leptin resistant rats to HF-induced obesity., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

To test the hypothesis that exercise increases central leptin signaling, and thus reduces dietary weight gain in an aged obese model, we assessed the effects of voluntary wheel running (WR) in 23-month-old F344×BN rats fed a 60% high-fat (HF) diet for 3 months. After 2 months on the HF diet, half of the rats were provided access to running wheels for 2 weeks while the other half remained sedentary. Following the removal of the wheels, physical performance was evaluated, and 4 weeks later leptin signaling was assessed in hypothalamus and VTA after an acute bout of WR. Introduction of a HF diet led to prolonged hyperphagia (63.9 ± 7.8 kcal/day on chow diet vs. 88.1 ± 8.2 kcal/day on high-fat diet (when food intake stabilized), p < 0.001). As little as 9 (ranging to 135) wheel revolutions per day significantly reduced caloric consumption of HF food (46.8 ± 11.2 kcal/day) to a level below that on chow diet (63.9 ± 7.8 kcal/day, p < 0.001). After 2 weeks of WR, body weight was significantly reduced (7.9 ± 2.1% compared with prerunning weight, p < 0.001), and physical performance (latency to fall from an incline plane) was significantly improved (p = 0.04). WR significantly increased both basal (p = 0.04) and leptin-stimulated (p = 0.001) STAT3 phosphorylation in the ventral tegmental area (VTA), but not in the hypothalamus. Thus, in aged dietary obese rats, the act but not the extent of voluntary WR is highly effective in reversing HF consumption, decreasing body weight, and improving physical performance. It appears to trigger a response that substitutes for the reward of highly palatable food that may be mediated by increased leptin signaling in the VTA., (Copyright © 2010 S. Karger AG, Basel.)

Short-term pharmacological melanocortin activation deters diet-induced obesity (DIO) effectively in rodents. However, whether central pro-opiomelanocortin (POMC) gene transfer targeted to the hypothalamus or hindbrain nucleus of the solitary track (NTS) can combat chronic dietary obesity has not been investigated. Four-weeks-old Sprague-Dawley rats were fed a high fat diet for 5 months, and then injected with either the POMC or control vector into the hypothalamus or NTS, and body weight and food intake recorded for 68 days. Insulin sensitivity, glucose metabolism and adrenal indicators of central sympathetic activation were measured, and voluntary wheel running (WR) assessed. Whereas the NTS POMC-treatment decreased cumulative food consumption and caused a sustained weight reduction over 68 days, the hypothalamic POMC-treatment did not alter cumulative food intake and produced weight loss only in the first 25 days. At death, only the NTS-POMC rats had a significant decrease in fat mass. They also displayed enhanced glucose tolerance, lowered fasting insulin and increased QUICK value, and elevated adrenal indicators of central sympathetic activation. Moreover, the NTS-POMC animals exhibited a near 20% increase in distance ran relative to the respective controls, but the ARC-POMC rats did not. In conclusion, POMC gene transfer to the NTS caused modest anorexia, persistent weight loss, improved insulin sensitivity, and increased propensity for WR in DIO rats. These metabolic improvements may involve stimulation of energy expenditure via centrally regulated sympathetic outflow. The similar POMC treatment in the hypothalamus had minimal long-term physiological or metabolic impact. Thus, melanocortin activation in the brainstem NTS region effectively ameliorates chronic dietary obesity whilst that in the hypothalamus fails to do so., ((c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

Voluntary wheel running (WR) is a form of physical activity in rodents that influences ingestive behavior. This study examined the effects of WR on dietary preference and the potential role of leptin in mediating these effects. In a two-diet choice paradigm in which both palatable high-fat (HF) food and standard laboratory chow were provided ad libitum, rats displayed a strong preference for the former and chose to eat almost exclusively the HF diet over chow in sedentary conditions. With free access to running wheels, however, rats exhibited no preference for the HF food and consumed equal gram amounts of both chow and HF diets. The total daily caloric consumption during WR in the dietary choice protocol was equivalent to the amount of calories consumed daily by WR rats with only chow or only HF diet available, yet significantly less than sedentary chow caloric consumption. Two days after initiating WR, leptin signal transduction was examined in multiple selected brain sites following leptin injection into the third cerebral ventricle. The maximal leptin-stimulated STAT3 phosphorylation was enhanced only in the ventral tegmental area (VTA), but not in the arcuate nucleus, lateral hypothalamus, dorsal medial or ventral medial hypothalamus, or substantia nigra. In conclusion, wheel running appears to act either as an independent reinforcing factor or as a more favored activity to substitute for the consumption of a palatable HF diet, thus eliminating the preference for the HF food. Moreover, WR enhances leptin signaling specifically in the VTA, suggestive of a WR-evoked mechanism of heightened leptin function in the VTA to curb the drive to consume palatable HF foods., (Copyright 2010 Elsevier Inc. All rights reserved.)

Central melanocortins (MC) evoke potent but transient anorectic responses with tachyphylaxis developing within days. We hypothesized that intermittent therapy using the MC analog, melanotan II (MTII), would minimize the tachyphylaxis and enhance the long-term efficacy of MTII treatment. F344/BN rats were infused with MTII or vehicle into the lateral ventricle by mini pump for 14 days. Half the MTII-infused rats were then given vehicle (MTII-On/Off), while the remaining received fresh MTII (MTII-On) for 10 days. Finally, pumps in both groups were replaced with ones containing fresh MTII for an additional 6 days. The first MTII application induced a 30% food reduction that attenuated within 5 days. Reapplication of MTII in MTII-On/Off rats, after the off period, invoked a new and equally robust anorectic response while continuation of MTII supplement in the MTII-On group did not change food intake from the control level. Body weights decreased similarly in both MTII groups at termination (day 30). Hypothalamic MC3 receptor, AgRP, and POMC expressions were unchanged, but MC4 receptor expression was diminished by 25%, and adiposity reduced by 80% in both MTII groups. Acetyl-CoA carboxylase 1 phosphorylation was elevated in perirenal fat by over 10 fold with either MTII treatment. In conclusion, intermittent MTII treatment preserves anorectic responses but does not prevent tachyphylaxis, whereas constant MTII application blunts further food response after the initial tachyphylaxis. Either form of MTII administration results in significant weight and adiposity reductions, involving perhaps fatty acid oxidation within specific adipose tissues., (Published by Elsevier Inc.)

Endocannabinoids (EC) are involved in regulating energy homeostasis, particularly in promoting hyperphagia and the consumption of a palatable diet. We have previously shown that rats given a high-fat (HF) diet display a transient hyperphagia that is normalized by a process partially dependent on leptin. We now propose that the induction of this hyperphagia is mediated, at least partially, by the EC signaling system. Obesity, including diet-induced and age-related, is associated with dysregulation of the EC system, and obese rodent models are hypersensitive to a cannabinoid-1 (CB1) receptor antagonist. This suggests that aged rats will be more responsive to the anorectic effects of a CB1 receptor antagonist. To test this, we examined the responsiveness to CB1 receptor antagonist, AM251, in young and aged rats during two experimental paradigms. First, we administered AM251 simultaneously with the introduction of an HF diet. Second, AM251 treatment began after the establishment of diet-induced obesity. Responses were measured by changes in body weight and composition, calorie intake, serum leptin, and biochemical indicators. The results demonstrated three key findings. 1) CB1 receptor activity contributes to the hyperphagia seen with the introduction of an HF diet. 2) Increased AM251 sensitivity and efficacy is increased with age and HF feeding, with the greatest responsiveness observed in HF-fed, aged rats. 3) AM251 sensitivity is elevated to a greater extent with HF diet than with established obesity. Thus, both age and an HF diet are associated with enhanced anorectic responses to AM251, but the underlying mechanism of these responses remains speculative.