Effects of systemic oxytocin and beta-3 receptor agonist (CL 316243) treatment on body weight and adiposity in male diet-induced obese rats.

Previous studies have implicated hindbrain oxytocin (OT) receptors in the control of food intake and brown adipose tissue (BAT) thermogenesis. We recently demonstrated that hindbrain [fourth ventricle (4V)] administration of oxytocin (OT) could be used as an adjunct to drugs that directly target beta-3 adrenergic receptors (β3-AR) to elicit weight loss in diet-induced obese (DIO) rodents. What remains unclear is whether systemic OT can be used as an adjunct with the β3-AR agonist, CL 316243, to increase BAT thermogenesis and elicit weight loss in DIO rats.

Sympathetic Innervation of Interscapular Brown Adipose Tissue Is Not a Predominant Mediator of Oxytocin-Induced Brown Adipose Tissue Thermogenesis in Female High Fat Diet-Fed Rats.

Recent studies have indicated that hindbrain [fourth ventricle (4V)] administration of the neurohypophyseal hormone, oxytocin (OT), reduces body weight, energy intake and stimulates interscapular brown adipose tissue temperature (T) in male diet-induced obese (DIO) rats. What remains unclear is whether chronic hindbrain (4V) OT can impact body weight in female high fat diet-fed (HFD) rodents and whether this involves activation of brown adipose tissue (BAT). We hypothesized that OT-elicited stimulation of sympathetic nervous system (SNS) activation of interscapular brown adipose tissue (IBAT) contributes to its ability to activate BAT and reduce body weight in female high HFD-fed rats.

Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of OT-elicited reductions of body weight gain and adiposity in male diet-induced obese rats.

Recent studies indicate that central administration of oxytocin (OT) reduces body weight (BW) in high fat diet-induced obese (DIO) rodents by reducing energy intake and increasing energy expenditure (EE). Previous studies in our lab have shown that administration of OT into the fourth ventricle (4V; hindbrain) elicits weight loss and stimulates interscapular brown adipose tissue temperature (T) in DIO rats. We hypothesized that OT-elicited stimulation of sympathetic nervous system (SNS) activation of IBAT contributes to its ability to activate BAT and reduce BW in DIO rats.

Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of oxytocin-elicited reductions of body weight and adiposity in male diet-induced obese mice.

Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (T, a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT.

Hindbrain Administration of Oxytocin Reduces Food Intake, Weight Gain and Activates Catecholamine Neurons in the Hindbrain Nucleus of the Solitary Tract in Rats.

Existing studies show that CNS oxytocin (OT) signaling is important in the control of energy balance, but it is unclear which neurons may contribute to these effects. Our goals were to examine (1) the dose-response effects of acute OT administration into the third (3V; forebrain) and fourth (4V; hindbrain) ventricles to assess sensitivity to OT in forebrain and hindbrain sites, (2) the extent to which chronic 4V administration of OT reduces weight gain associated with the progression of diet-induced obesity, and (3) whether nucleus tractus solitarius (NTS) catecholamine neurons are downstream targets of 4V OT. Initially, we examined the dose-response effects of 3V and 4V OT (0.

Effects of Combined Oxytocin and Beta-3 Receptor Agonist (CL 316243) Treatment on Body Weight and Adiposity in Male Diet-Induced Obese Rats.

Previous studies have indicated that oxytocin (OT) reduces body weight in diet-induced obese (DIO) rodents through reductions in energy intake and increases in energy expenditure. We recently demonstrated that hindbrain [fourth ventricular (4V)] administration of OT evokes weight loss and elevates interscapular brown adipose tissue temperature (T ) in DIO rats. What remains unclear is whether OT can be used as an adjunct with other drugs that directly target beta-3 receptors in IBAT to promote BAT thermogenesis and reduce body weight in DIO rats.

Chronic hindbrain administration of oxytocin elicits weight loss in male diet-induced obese mice.

Previous studies indicate that oxytocin (OT) administration reduces body weight in high-fat diet (HFD)-induced obese (DIO) rodents through both reductions in food intake and increases in energy expenditure. We recently demonstrated that chronic hindbrain [fourth ventricular (4V)] infusions of OT evoke weight loss in DIO rats. Based on these findings, we hypothesized that chronic 4V OT would elicit weight loss in DIO mice.

Repetitive Blast Promotes Chronic Aversion to Neutral Cues Encountered in the Peri-Blast Environment.

Repetitive mild traumatic brain injury (mTBI) has been called the "signature injury" of military service members in the Iraq and Afghanistan wars and is highly comorbid with post-traumatic stress disorder (PTSD). Correct attribution of adverse blast-induced mTBI and/or PTSD remains challenging. Pre-clinical research using animal models can provide important insight into the mechanisms by which blast produces injury and dysfunction-but only to the degree by which such models reflect the human experience.

Intranasal oxytocin reduces weight gain in diet-induced obese prairie voles.

Oxytocin (OT) elicits weight loss in diet-induced obese (DIO) rodents, nonhuman primates and humans by reducing food intake and increasing energy expenditure. In addition to being important in the regulation of energy balance, OT is involved in social behaviors including parent-infant bonds, friendships, and pair bonds. However, the impact of social context on susceptibility to diet-induced obesity (DIO) and feeding behavior (including food sharing) has not been investigated in a rodent model that forms strong social bonds (i.

Use of the PET ligand florbetapir for in vivo imaging of pancreatic islet amyloid deposits in hIAPP transgenic mice.

Aims/hypothesis: Islet amyloid deposits contribute to beta cell dysfunction and death in most individuals with type 2 diabetes but non-invasive methods to determine the presence of these pathological protein aggregates are currently not available. Therefore, we examined whether florbetapir, a radiopharmaceutical agent used for detection of amyloid-β deposits in the brain, also allows identification of islet amyloid in the pancreas.

Methods: Saturation binding assays were used to determine the affinity of florbetapir for human islet amyloid polypeptide (hIAPP) aggregates in vitro.

Chronic hindbrain administration of oxytocin is sufficient to elicit weight loss in diet-induced obese rats.

Oxytocin (OT) administration elicits weight loss in diet-induced obese (DIO) rodents, nonhuman primates, and humans by reducing energy intake and increasing energy expenditure. Although the neurocircuitry underlying these effects remains uncertain, OT neurons in the paraventricular nucleus are positioned to control both energy intake and sympathetic nervous system outflow to interscapular brown adipose tissue (BAT) through projections to the hindbrain nucleus of the solitary tract and spinal cord. The current work was undertaken to examine whether central OT increases BAT thermogenesis, whether this effect involves hindbrain OT receptors (OTRs), and whether such effects are associated with sustained weight loss following chronic administration.

Chronic CNS oxytocin signaling preferentially induces fat loss in high-fat diet-fed rats by enhancing satiety responses and increasing lipid utilization.

Based largely on a number of short-term administration studies, growing evidence suggests that central oxytocin is important in the regulation of energy balance. The goal of the current work is to determine whether long-term third ventricular (3V) infusion of oxytocin into the central nervous system (CNS) is effective for obesity prevention and/or treatment in rat models. We found that chronic 3V oxytocin infusion between 21 and 26 days by osmotic minipumps both reduced weight gain associated with the progression of high-fat diet (HFD)-induced obesity and elicited a sustained reduction of fat mass with no decrease of lean mass in rats with established diet-induced obesity.

Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition.

Intranasal insulin has shown efficacy in patients with Alzheimer's disease (AD), but there are no preclinical studies determining whether or how it reaches the brain. Here, we showed that insulin applied at the level of the cribriform plate via the nasal route quickly distributed throughout the brain and reversed learning and memory deficits in an AD mouse model. Intranasal insulin entered the blood stream poorly and had no peripheral metabolic effects.

Circulating irisin levels and muscle FNDC5 mRNA expression are independent of IL-15 levels in mice.

Interleukin-15 (IL-15) and irisin are exercise-induced myokines that exert favorable effects on energy expenditure and metabolism. IL-15 can induce PGC-1α expression, which in turn induces expression of irisin and its precursor, FNDC5. Therefore, the present study tested the hypothesis that increases in circulating irisin levels and muscle FNDC5 mRNA expression are dependent on IL-15.

Assessment of murine exercise endurance without the use of a shock grid: an alternative to forced exercise.

Using laboratory mouse models, the molecular pathways responsible for the metabolic benefits of endurance exercise are beginning to be defined. The most common method for assessing exercise endurance in mice utilizes forced running on a motorized treadmill equipped with a shock grid. Animals who quit running are pushed by the moving treadmill belt onto a grid that delivers an electric foot shock; to escape the negative stimulus, the mice return to running on the belt.

IL-15 is required for postexercise induction of the pro-oxidative mediators PPARδ and SIRT1 in male mice.

Physical exercise induces transient upregulation of the pro-oxidative mediators peroxisome proliferator-activated receptor-δ (PPARδ), silent information regulator of transcription (sirtuin)-1 (SIRT1), PPARγ coactivator 1α (PGC-1α), and PGC-1β in skeletal muscle. To determine the role of the cytokine IL-15 in acute postexercise induction of these molecules, expression of these factors after a bout of exhaustive treadmill running was examined in the gastrocnemius muscle of untrained control and IL-15-knockout (KO) mice. Circulating IL-15 levels increased transiently in control mice after exercise.

IL-15 overexpression promotes endurance, oxidative energy metabolism, and muscle PPARδ, SIRT1, PGC-1α, and PGC-1β expression in male mice.

Endurance exercise initiates a pattern of gene expression that promotes fat oxidation, which in turn improves endurance, body composition, and insulin sensitivity. The signals from exercise that initiate these pathways have not been completely characterized. IL-15 is a cytokine that is up-regulated in skeletal muscle after exercise and correlates with leanness and insulin sensitivity.

Alterations in activity and energy expenditure contribute to lean phenotype in Fischer 344 rats lacking the cholecystokinin-1 receptor gene.

CCK is hypothesized to inhibit meal size by acting at CCK1 receptors (CCK1R) on vagal afferent neurons that innervate the gastrointestinal tract and project to the hindbrain. Earlier studies have shown that obese Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which carry a spontaneous null mutation of the CCK1R, are hyperphagic and obese. Recent findings show that rats with CCK1R-null gene on a Fischer 344 background (Cck1r(-/-)) are lean and normophagic.

Peripheral oxytocin suppresses food intake and causes weight loss in diet-induced obese rats.

Growing evidence suggests that oxytocin plays an important role in the regulation of energy balance and that central oxytocin administration induces weight loss in diet-induced obese (DIO) animals. To gain a better understanding of how oxytocin mediates these effects, we examined feeding and neuronal responses to oxytocin in animals rendered obese following exposure to either a high-fat (HFD) or low-fat diet (LFD). Our findings demonstrate that peripheral administration of oxytocin dose-dependently reduces food intake and body weight to a similar extent in rats maintained on either diet.

Overexpression of interleukin-15 in mice promotes resistance to diet-induced obesity, increased insulin sensitivity, and markers of oxidative skeletal muscle metabolism.

Interleukin-15 (IL-15) is a cytokine that is highly expressed in skeletal muscle. In addition to its well-characterized effects on innate immunity, IL-15 has been proposed to modulate skeletal muscle and adipose tissue mass, as well as insulin sensitivity. In the present study, an IL-15 gain-of-function model, transgenic mice with skeletal muscle-specific oversecretion of IL-15 (IL-15 Tg mice), was utilized to test the hypotheses that IL-15 promotes insulin sensitivity and resistance to diet-induced obesity (DIO) by increasing circulating adiponectin levels, and that IL-15 regulates skeletal muscle metabolism without inducing overt muscle hypertrophy.

Changes in body composition in response to challenges during aging in rats.

Body composition changes over the lifespan of Brown Norway rats, in patterns similar to those of humans. Young adults are lean, with little fat, much of which is intra-abdominal. As they age, rats exhibit linear growth, and both lean and fat mass increase until late middle to early old age.

Serum and muscle interleukin-15 levels decrease in aging mice: correlation with declines in soluble interleukin-15 receptor alpha expression.

Interleukin-15 (IL-15) is a skeletal muscle-derived cytokine with favorable effects on muscle mass and body composition. Modulation of IL-15 levels has been suggested as a treatment for sarcopenia and age-associated increases in adiposity. However, it is unclear whether IL-15 levels change during aging, as measurement of IL-15 at physiological concentrations in mice has been technically difficult, and translational regulation of IL-15 is complex.

Peripheral ghrelin treatment stabilizes body weights of senescent male Brown Norway rats at baseline and after surgery.

Unintentional weight loss may occur spontaneously in older humans and animals. Further weight losses after surgery or illness in the older patients result in increased morbidity, mortality, and hospital readmission rate. A growing body of work has shown increased appetite and weight gain in response to administration of ghrelin, the "hunger hormone.

Mechanisms of the anorexia of aging in the Brown Norway rat.

Aging is associated with a loss of the ability to maintain homeostasis in response to physiologic and environmental disturbances. Age-related dysregulation of food intake and energy balance appears to be the result of impaired responsiveness of hypothalamic integrative circuitry to metabolic cues, which can lead to lack of appropriate food intake (the anorexia of aging) and thus to inappropriate weight loss in response to acute or chronic illness or other stressors. Using the Brown Norway (BN) male rat model, we have shown that old animals fail to appropriately increase food intake after the metabolic challenge of a 72 h fast, resulting in the failure to re-gain lost body weight upon refeeding.