Ketogenic diets (KDs) are shown to benefit hepatic metabolism; however, their effect on the liver when combined with exercise is unknown. We investigated the effects of a KD versus a “western” diet (WD) on markers of hepatic lipid metabolism and oxidative stress in exercising rats. Male and female Wistar rats with access to voluntary running wheels were randomized to 3 groups (n = 8–14 per group): standard chow (SC; 17% fat), WD (42% fat), or KD (90.5% fat) for 7 weeks. Body fat percentage (BF%) was increased in WD and KD versus SC, although KD females displayed lower BF% versus WD (p ≤ 0.05). Liver triglycerides were higher in KD and WD versus SC but were attenuated in KD females versus WD (p ≤ 0.05). KD suppressed hepatic markers of de novo lipogenesis (fatty acid synthase, acetyl coenzyme A carboxylase) and increased markers of mitochondrial biogenesis/content (peroxisome proliferator activated receptor-1α, mitochondrial transcription factor A (TFAM), and citrate synthase activity). KD also increased hepatic glutathione peroxidase 1 and lowered oxidized glutathione. Female rats exhibited elevated hepatic markers of mitochondrial biogenesis (TFAM), mitophagy (light chain 3 II/I ratio, autophagy-related protein 12:5), and cellular energy homeostasis (phosphorylated 5′AMP-activated protein kinase/5′AMP-activated protein kinase) versus males. These data highlight that KD and exercise beneficially impacts hepatic metabolism and oxidative stress and merits further investigation. Novelty KD feeding combined with exercise improved hepatic oxidative stress, suppressed markers of de novo lipogenesis, and increased markers of mitochondrial content versus WD feeding. Males and females responded similarly to combined KD feeding and exercise. Female rats exhibited elevated hepatic markers of autophagy/mitophagy and energy homeostasis compared with male rats.

Effective treatments preventing brain neuroinflammatory diseases are lacking. Resistance-exercise training (RT) ameliorates mild cognitive impairment (MCI), a forerunner to neuroinflammatory diseases. However, few studies have addressed the molecular basis by which RT abates MCI. Thus experiments were performed to identify some molecular changes occurring in response to RT in young, female Wistar rats. To induce MCI, intraventricular lipopolysaccharide (LPS) injections were used to increase dentate gyrus inflammation, reflected by significantly increased TNF-α (~400%) and IL-1β (~1,500%) mRNA ( P < 0.0001) after 6 wk. Five days after LPS injections, half of LPS-injected rats performed RT by ladder climbing for 6 wk, 3 days/wk, whereas half remained without ladders. RT for 6 wk increased lean body mass percentage ( P < 0.05), individual muscle masses (gastrocnemius and tibialis anterior) ( P < 0.05), and maximum lifting capacity ( P < 0.001). The RT group, compared with sedentary controls, had 1) ameliorated spatial learning deficits ( P < 0.05), 2) increased dentate gyrus phosphorylation of IGF-1R, protein kinase B, and GSK-3β proteins ( P < 0.05), components of downstream IGF-1 signaling, and 3) increased dentate gyrus synaptic plasticity marker synapsin protein ( P < 0.05). Two follow-up experiments (without LPS) characterized dentate gyrus signaling during short-term RT. Twenty-four hours following the third workout in a 1-wk training duration, phosphorylation of ERK1/2 and GSK-3β proteins, as well as proliferation marker protein, PCNA, were significantly increased ( P < 0.05). Similar changes did not occur in a separate group of rats following a single RT workout. Taken together, these data indicate that RT ameliorates LPS-induced MCI after RT, possibly mediated by increased IGF-1 signaling pathway components within the dentate gyrus. NEW & NOTEWORTHY The data suggest that resistance-exercise training restores cognitive deficits induced by lipopolysaccharides and can activate associated IGF-1 signaling in the dentate gyrus. Our data show, for the first time, that as few as three resistance-exercise workouts (spread over 1 wk) can activate IGF-1 downstream signaling and increase proliferation marker PCNA in the dentate gyrus.

Mild cognitive impairment (MCI) designates the boundary area between cognitive function in natural aging and dementia, and this is viewed as a therapeutic window to prevent the occurrence of dementia. The current study investigated the neurocognitive effects of oral creatine (Cr) supplementation in young female Wistar rats that received intracerebroventricular injections of lipopolysaccharide (LPS) to mimic MCI. Neuromolecular changes within the dentate gyrus were analyzed following behavioral testing. We also investigated both neurocognitive and neuromolecular changes following Cr supplementation in the absence of LPS in young female Wistar rats to further investigate mechanisms. Interestingly, based on trial 2 of Barnes maze test, Cr supplementation ameliorated spatial learning and memory deficit induced by LPS, shown by decreased latency time and errors to reach the escape box (p < 0.0001, n = 12). Cr supplementation also attenuated recognition memory deficit induced by LPS, shown by increased amount of time taken to explore the new object (p = 0.002, n = 12) during novel object recognition testing. Within the dentate gyrus, Cr supplementation in LPS injected rats upregulated mTORC1 signaling (p = 0.026 for mTOR phosphorylation, p = 0.002 for p70S6K phosphorylation, n = 8) as well as the synapsin (p = 0.008) and PSD-95 synaptic proteins (p = 0.015), in comparisons to LPS injected rats. However, Cr supplementation failed to further enhance spatial memory and recognition memory in the absence of LPS. In conclusion, Cr ameliorates LPS-induced cognitive impairment in a rodent MCI model. Mechanistically, these phenotypic effects may, in part, be mitigated via an upregulation of mTORC1 signaling, and an enhancement in synaptogenesis in the dentate gyrus. While preliminary, these findings may inform future research investigating neurocognitive effects of Cr for MCI patients.

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 female WD offspring In contrast, no wheel-running differences in F 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 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 in the VTA. Body fat, leptin, and insulin were increased in male, but not in female, F WD offspring. Recombinant virus (rAAV) leptin antagonism in the VTA decreased wheel running in standard diet but not in WD F female offspring. Analysis of F offspring found no differences in wheel running or adiposity in male or female offspring, suggesting that changes in the F generation were related to 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.

Neuroinflammation is an early detectable marker of mild cognitive impairment, the transition state between normal cognition and dementia. Resistance-exercise training can attenuate the cognitive decline observed in patients with mild cognitive impairment. However, the underlying mechanisms of resistance training effects are largely unknown. To further elucidate mechanisms of the known cognitive health benefits from resistance-exercise training, we tested if three weeks of resistance-exercise training could ameliorate lipopolysaccharide-induced neuroinflammation. Five-week-old female Wistar rats received intracerebroventricular injections of lipopolysaccharides to induce neuroinflammation and cognitive impairment. Rats then underwent three weeks of progressive ladder climbing to recapitulate resistance-exercise training in humans. Cognition was assessed towards the end of the training period by novelty object recognition testing. Neuroinflammation was measured one and 24-hours after the last resistance-exercise training workout. Resistance-exercise training ameliorated cognitive impairment, diminished lipopolysaccharide-induced neuroinflammatory cytokine expression, and attenuated astrocyte remodeling in the dentate gyrus 24-hours post exercise. Here, we provide evidence that the ladder-climbing model of resistance-exercise training in rats can improve cognition as early as three weeks. Additionally, these data support the hypothesis that resistance exercise can reduce lipopolysaccharide-induced neuroinflammation in the dentate gyrus.

Physical activity (PA) is a non-invasive, cost-effective means of reducing chronic disease. Most US citizens fail to meet PA guidelines, and individuals experiencing chronic stress are less likely to be physically active. To better understand the barriers to maintaining active lifestyles, we sought to determine the extent to which short- versus long-term PA increases stress- and aversion-related markers in wild-type (WT) and low voluntary running (LVR) rats, a unique genetic model of low physical activity motivation. Here, we tested the effects of 1 and 4 weeks of voluntary wheel-running on physiological, behavioral, and molecular measures of stress and Hypothalamic Pituitary Adrenal (HPA)-axis responsiveness (corticosterone levels, adrenal wet weights, and fecal boli counts). We further determined measures of aversion-related signaling (kappa opioid receptor, dynorphin, and corticotropin releasing hormone mRNA expression) in the basolateral amygdala (BLA), a brain region well characterized for its role in anxiety and aversion. Compared to sedentary values, 1, but not 4 weeks of voluntary wheel-running increased adrenal wet weights and plasma corticosterone levels, suggesting that HPA responsiveness normalizes following long-term PA. BLA mRNA expression of prodynorphin (Pdyn) was significantly elevated in WT and LVR rats following 1 week of wheel-running compared to sedentary levels, suggesting that aversion-related signaling is elevated following short- but not long-term wheel-running. In all, it appears that the stress effects of acute PA may increase molecular markers associated with aversion in the BLA, and that LVR rats may be more sensitive to these effects, providing a potential neural mechanism for their low PA motivation.

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