Emerging research has shown that subtle factors during pregnancy and gestation can influence long-term health in offspring. In an attempt to be proactive, we set out to explore whether a nonpharmacological intervention, perinatal exercise, might improve offspring health. Female mice were separated into sedentary or exercise cohorts, with the exercise cohort having voluntary access to a running wheel prior to mating and during pregnancy and nursing. Offspring were weaned, and analyses were performed on the mature offspring that did not have access to running wheels during any portion of their lives. Perinatal exercise caused improved glucose disposal following an oral glucose challenge in both female and male adult offspring (P Ͻ 0.05 for both). Blood glucose concentrations were reduced to lower values in response to an intraperitoneal insulin tolerance test for both female and male adult offspring of parents with access to running wheels (P Ͻ 0.05 and P Ͻ 0.01, respectively). Male offspring from exercised dams showed increased percent lean mass and decreased fat mass percent compared with male offspring from sedentary dams (P Ͻ 0.01 for both), but these parameters were unchanged in female offspring. These data suggest that short-term maternal voluntary exercise prior to and during healthy pregnancy and nursing can enhance long-term glucose homeostasis in offspring.running; pregnancy; programming; mice IN 2007, 23.5 MILLION PEOPLE in the US were estimated to have diabetes, and this number is increasing (4). Interestingly, and what is often underappreciated, is that the metabolic status of an individual is decided not only by their inherited genes, nutritional intake, and physical exercise but also by maternal nutrition and obesity during pregnancy. In 1992, Hales and Barker (18) put forth the thrifty phenotype hypothesis that suggested that malnourished pregnant mothers produce smaller offspring that have a higher incidence of obesity, diabetes, and heart disease in adulthood. This hypothesis has since been modified to the developmental origins of health and disease (DOHaD) (15,17,18).The DOHaD suggests that the maternal environment and fetal programming lead to a higher incidence of several diseases later in life (14, 16). A growing number of studies have been designed to provide evidence for the negative impact of DOHaD, using mice, rats, and sheep as animal models (11,12,31,38). Many of these studies are directed at malnutrition through protein restriction or physical stressors that produce similar effects (8,11,34,44,45), but more recent studies are elucidating the metabolic effects of high-fat diet consumption during pregnancy on offspring (22,38,44,48).It has been known since Hippocrates and Galen that physical activity is an important component of a healthy lifestyle (33). However, knowledge about the contributions of maternal exercise during pregnancy and the long-term consequences on offspring is minimal. In both rats and mice, maternal exercise during pregnancy can improve brain physiology and cognition...

A reduction in calorie intake (Caloric restriction), appears to consistently decrease the biological rate of aging in a variety of organisms as well as protect against age-associated diseases including chronic inflammatory disorders such as cardiovascular disease and diabetes. Although the mechanisms behind this observation are not fully understood, identification of the main metabolic pathways affected by caloric restriction has generated interest in finding molecular targets that could be modulated by caloric restriction mimetics. This review describes the general concepts of caloric restriction and caloric restriction mimetics as well as discusses evidence related to their effects on inflammation and chronic inflammatory disorders. Additionally, emerging evidence related to the effects of caloric restriction on periodontal disease in non-human primates is presented. While the implementation of this type of dietary intervention appears to be challenging in our modern society where obesity is a major public health problem, caloric restriction mimetics could offer a promising alternative to control and perhaps prevent several chronic inflammatory disorders including periodontal disease.

Darnall RA, Schneider RW, Tobia CM, Zemel BM. Arousal from sleep in response to intermittent hypoxia in rat pups is modulated by medullary raphe GABAergic mechanisms. Am J Physiol Regul Integr Comp Physiol 302: R551-R560, 2012. First published December 7, 2011; doi:10.1152/ajpregu.00506.2011Arousal is an important defense against hypoxia during sleep. Rat pups exhibit progressive arousal impairment (habituation) with multiple hypoxia exposures. The mechanisms are unknown. The medullary raphe (MR) is involved in autonomic functions, including sleep, and receives abundant GABAergic inputs. We hypothesized that inhibiting MR neurons with muscimol, a GABA A receptor agonist, or preventing GABA reuptake with nipecotic acid, would impair arousal and enhance arousal habituation and that blocking GABA A receptors with bicuculline would enhance arousal and attenuate habituation. Postnatal day 15 (P15) to P25 rat pups were briefly anesthetized, and microinjections with aCSF, muscimol, bicuculline, or nipecotic acid were made into the MR. After a ϳ30-min recovery, pups were exposed to four 3-min episodes of hypoxia separated by 6 min of normoxia. The time to arousal from the onset of hypoxia (latency) was determined for each trial. Latency progressively increased across trials (habituation) in all groups. The overall latency was greater after muscimol and nipecotic acid compared with aCSF, bicuculline, or noninjected controls. Arousal habituation was reduced after bicuculline compared with aCSF, muscimol, nipecotic acid, or noninjected pups. Increases in latency were mirrored by decreases in chamber [O2] and oxyhemoglobin saturation. Heart rate increased during hypoxia and was greatest in muscimol-injected pups. Our results indicate that the MR plays an important, not previously described, role in arousal and arousal habituation during hypoxia and that these phenomena are modulated by GABAergic mechanisms. Arousal habituation may contribute to sudden infant death syndrome, which is associated with MR serotonergic and GABAergic receptor dysfunction.␥-aminobutyric acid; sudden infant death syndrome; GABAA receptor; habituation IN HUMAN INFANTS, AROUSAL is an important protective mechanism against hypoxia during sleep. Spontaneous arousals and those in response to exogenous stimuli are affected by many factors: sleep position (3, 29, 37), sleep efficiency (30), prenatal exposure to cigarette smoking (28, 38), and stage of development (39). It has been hypothesized that arousal impairment may play an important role in the etiology of sudden infant death syndrome (SIDS) (32,40,43,46). Moreover, many SIDS infants have repeated episodes of apnea and hypoxia in the days or weeks prior to death (44,56). We propose that repeated exposure to hypoxia during sleep leads to progressive lengthening of the time to arousal in response to hypoxia that might contribute to sudden death.We and others have shown in newborn and infant rodents (17, 18, 21), lambs (25,41,42), and piglets (71) that repeated brief exposures to mild hypoxia result in...

Arousal is an important survival mechanism when infants are confronted with hypoxia during sleep. Many sudden infant death syndrome (SIDS) infants are exposed to repeated episodes of hypoxia before death and have impaired arousal mechanisms. We hypothesized that repeated exposures to hypoxia would cause a progressive blunting of arousal, and that a reversal of this process would occur if the hypoxia was terminated at the time of arousal. P5 (postnatal age of 5 days), P15, and P25 rat pups were exposed to either eight trials of hypoxia (3 min 5% O(2) alternating with room air) (group A), or three hypoxia trials as in group A, followed by five trials in which hypoxia was terminated at arousal (group B). In both groups A and B, latency increased over the first four trials of hypoxia, but reversed in group B animals during trials 5-8. Progressive arousal blunting was more pronounced in the older pups. The effects of intermittent hypoxia on heart rate also depended on age. In the older pups, heart rate increased with each hypoxia exposure. In the P5 pups, however, heart rate decreased during hypoxia and did not return to baseline between exposures, resulting in a progressive fall of baseline values over successive hypoxia exposures. In the group B animals, heart rate changes during trials 1-4 also reversed during trials 5-8. We conclude that exposure to repeated episodes of hypoxia can cause progressive blunting of arousal, which is reversible by altering the exposure times to hypoxia and the period of recovery between hypoxia exposures.

Arousal from sleep is a critical defense mechanism when infants are exposed to hypoxia, and an arousal deficit has been postulated as contributing to the etiology of the sudden infant death syndrome (SIDS). The brainstems of SIDS infants are deficient in serotonin (5-HT) and tryptophan hydroxylase (TPH) and have decreased binding to 5-HT receptors. This study explores a possible connection between medullary 5-HT neuronal activity and arousal from sleep in response to hypoxia. Medullary raphe 5-HT neurons were eliminated from neonatal rat pups with intracisterna magna (CM) injections of 5,7-dihydroxytryptamine (DHT) at P2-P3. Each pup was then exposed to four episodes of hypoxia during sleep at three developmental ages (P5, P15, and P25) to produce an arousal response. Arousal, heart rate, and respiratory rate responses of DHT-injected pups were compared with pups that received CM artificial cerebrospinal fluid (aCSF) and those that received DHT but did not have a significant reduction in medullary 5-HT neurons. During each hypoxia exposure, the time to arousal from the onset of hypoxia (latency) was measured together with continuous measurements of heart and respiratory rates, oxyhemoglobin saturation, and chamber oxygen concentration. DHT-injected pups with significant losses of medullary 5-HT neurons exhibited significantly longer arousal latencies and decreased respiratory rate responses to hypoxia compared with controls. These results support the hypothesis that in newborn and young rat pups, 5-HT neurons located in the medullary raphe contribute to the arousal response to hypoxia. Thus alterations medullary 5-HT mechanisms might contribute to an arousal deficit and contribute to death in SIDS infants.