The skin, the largest organ, functions as a primary defense mechanism. Epidermal stem cells supply undifferentiated keratinocytes that differentiate as they migrate toward the outermost skin layer. Although such a replenishment process is disrupted in various human skin diseases, its underlying mechanisms remain elusive. With high-resolution live imaging and in vivo manipulations, we revealed that Notch signaling between keratinocytes is mediated by signaling filopodia called cytonemes and is essential for proper keratinocyte differentiation and proliferation. Inhibiting keratinocyte cytonemes reduced Notch expression within undifferentiated keratinocytes, leading to abnormal differentiation and hyperproliferation, resembling human skin disease phenotypes. Overproduction of Interleukin (IL)-17 signal, associated with skin diseases like psoriasis , induces psoriatic phenotypes via cytonemes in zebrafish. Our study suggests that intercellular signaling between keratinocytes through cytonemes is critical for epidermal maintenance, and its misregulation could be an origin of human skin diseases.

Circulating corticosteroids orchestrate stress adaptation, including inhibition of inflammation. While pathways governing corticosteroid biosynthesis and intracellular signaling are well understood, less is known about mechanisms controlling plasma corticosteroid transport. Here, we show that hepatocyte KLF15 (Kruppel-like factor 15) controls plasma corticosteroid transport and inflammatory responses through direct transcriptional activation of Serpina6, which encodes corticosteroid-binding globulin (CBG). Klf15-deficient mice have profoundly low CBG, reduced plasma corticosteroid binding capacity, and heightened mortality during inflammatory stress. These defects are completely rescued by reconstituting CBG, supporting that KLF15 works primarily through CBG to control plasma corticosterone homeostasis. To understand transcriptional mechanisms, we generated the first KLF15 cistromes using newly engineered Klf153xFLAG mice. Unexpectedly, liver KLF15 is predominantly promoter enriched, including Serpina6, where it binds a palindromic GC-rich motif, opens chromatin, and transactivates genes with minimal associated direct gene repression. Overall, we provide critical mechanistic insight into KLF15 function and identify a hepatocyte-intrinsic transcriptional module that potently regulates systemic corticosteroid transport and inflammation.

We sought to determine the effects of 12 months of power training on cognition, and whether improvements in body composition, muscle strength, and/or aerobic capacity (VO2peak) were associated with improvements in cognition in older adults with type 2 diabetes (T2D). Participants with T2D were randomized to power training or low-intensity sham exercise control condition, 3 days per week for 12 months. Cognitive outcomes included memory, attention/speed, executive function, and global cognition. Other relevant outcomes included VO2peak, strength, and whole body and regional body composition. One hundred and three adults with T2D (mean age 67.9 years; standard deviation [SD] 5.9; 50.5% women) were enrolled and analyzed. Unexpectedly, there was a nearly significant improvement in global cognition (p = .05) in the sham group relative to power training, although both groups improved over time (p < .01). There were significant interactions between group allocation and body composition or muscle strength in the models predicting cognitive changes. Therefore, after stratifying by group allocation, improvements in immediate memory were associated with increases in relative skeletal muscle mass (r = 0.38, p = .03), reductions in relative body fat (r = -0.40, p = .02), and increases in knee extension strength were directly related to changes in executive function (r = -0.41, p = .02) within the power training group. None of these relationships were present in the sham group (p > .05). Although power training did not significantly improve cognition compared to low-intensity exercise control, improvements in cognitive function in older adults were associated with hypothesized improvements in body composition and strength after power training.

Background: We examined the effect of power training on habitual, intervention and total physical activity (PA) levels in older adults with type 2 diabetes and their relationship to metabolic control. Materials and Methods: 103 adults with type 2 diabetes were randomized to receive supervised power training or sham exercise three times/week for 12 months. Habitual, intervention, and total PA, as well as insulin resistance (HOMA2-IR) and glycosylated hemoglobin (HbA1c), were measured. Results: Participants were aged 67.9 ± 5.5 yrs, with well-controlled diabetes (HbA1c = 7.1%) and higher than average habitual PA levels compared to healthy peers. Habitual PA did not change significantly over 12 months (p = 0.74), and there was no effect of group assignment on change over time in habitual PA over 0–6 (p = 0.16) or 0–6–12 months (p = 0.51). By contrast, intervention PA, leg press tonnage and total PA increased over both 6- and 12-month timepoints (p = 0.0001), and these changes were significantly greater in the power training compared to the sham exercise group across timepoints (p = 0.0001). However, there were no associations between changes in any PA measures over time and changes in metabolic profile. Conclusion: Structured high-intensity power training may be an effective strategy to enhance overall PA in this high-risk cohort.

The melanocortin 4 receptor (MC4R) plays a critical role in the long-term regulation of energy homeostasis, and mutations in the MC4R are the most common cause of monogenic obesity. However, the precise molecular and cellular mechanisms underlying the maintenance of energy balance within MC4R-expressing neurons are unknown. We recently reported that the MC4R localizes to the primary cilium, a cellular organelle that allows for partitioning of incoming cellular signals, raising the question of whether the MC4R functions in this organelle. Here, using mouse genetic approaches, we found that cilia were required specifically on MC4R-expressing neurons for the control of energy homeostasis. Moreover, these cilia were critical for pharmacological activators of the MC4R to exert an anorexigenic effect. The MC4R is expressed in multiple brain regions. Using targeted deletion of primary cilia, we found that cilia in the paraventricular nucleus of the hypothalamus (PVN) were essential to restrict food intake. MC4R activation increased adenylyl cyclase (AC) activity. As with the removal of cilia, inhibition of AC activity in the cilia of MC4R-expressing neurons of the PVN caused hyperphagia and obesity. Thus, the MC4R signaled via PVN neuron cilia to control food intake and body weight. We propose that defects in ciliary localization of the MC4R cause obesity in human inherited obesity syndromes and ciliopathies.

PURPOSE: We examined the effect of power training on long-term changes in physical activity (PA) in older adults with type 2 diabetes (T2D) during a 5-year follow-up of the GREAT2DO randomized control trial. METHODS: 103 participants with T2D and metabolic syndrome (51% male, 67.9 ±5.5 yrs) were randomized to receive power or sham exercise training, 3 times/week for 12 months and followed for another 5 years. During follow-up, the power group was supported to continue, and controls were crossed over to training, but neither group exercised under direct supervision. Total PA was assessed using the Physical Activity Scale for the Elderly and the Homeostasis model assessment: insulin resistance (HOMA2-IR) and glycosylated hemoglobin (HbA1c) were used as indices of IR and glucose homeostasis, respectively. RESULTS: Total PA decreased significantly during the follow-up period (p=0.0001), driven by reductions between 12 and 24 months when full supervision of exercise was withdrawn, followed by relative stability over the next 4 years. Engagement in resistance training (PRT) declined from 76% at 12 months in the original power training group to 43% of those assessed at the 6-year follow-up. Notably, 43% of the original sham group also reported engaging in PRT at 6 years. HbA1c, adjusted for total PA level over the 5 years, and diabetes medication usage were significantly lower at 72 vs. 12 months (p= 0.04), without any effect of original group assignment. However, there was no significant change over the follow-up period for HOMA2-IR, adjusted for PA and medication usage (p= 0.23). CONCLUSION: 5 years after withdrawal of fully supervised power training or sham exercise in initially inactive older adults with T2D, 43% of both groups were engaged in minimally-supervised resistance training in community sites. Although both groups reduced participation in structured exercise after withdrawal of direct supervision at 12 months, stability in Total PA level from 24-72 months along with persistence of PRT in 43% of older adults with diabetes and many progressive co-morbidities is notable and unexpected. We are unaware of any other study of unsupervised PRT in an older clinical cohort in which adherence rates of 43% have been achieved 6 years after initial randomization, accompanied by significant improvements in glucose control.

The Melanocortin-4 Receptor (MC4R) plays a critical role in the long-term regulation of energy homeostasis and mutations in MC4R are the most common cause of monogenic obesity. However, the precise molecular and cellular mechanisms underlying the maintenance of energy balance within MC4R expressing neurons are unknown. We recently reported that MC4R localizes to primary cilia, a cellular organelle that allows for partitioning of incoming cellular signals, raising the question of whether MC4R functions there. Here, using mouse genetic approaches, we found that cilia are required specifically on MC4R-expressing neurons to restrain feeding behavior. Moreover, these cilia were critical for pharmacological activators of MC4R to exert an anorexigenic effect. MC4R is expressed in multiple brain regions. Using targeted deletion of primary cilia, we found that cilia in the paraventricular nucleus (PVN) of the hypothalamus are essential to restrict food intake. MC4R activation increases adenylyl cyclase activity. Like removing cilia, inhibiting adenylyl cyclase activity in the cilia of MC4R-expressing neurons of the PVN caused hyperphagia and obesity. Thus, MC4R signals via cilia of PVN neurons to control food intake and body weight. We propose that defects in ciliary localization of MC4R cause obesity in human inherited obesity syndromes and ciliopathies.

Dementia affects 47 million individuals worldwide, and assuming the status quo is projected to rise to 150 million by 2050. Prevention of age-related cognitive impairment in older persons with lifestyle interventions continues to garner evidence but whether this can combat underlying neurodegeneration is unknown. The Study of Mental Activity and Resistance Training (SMART) trial has previously reported within-training findings; the aim of this study was to investigate the long-term neurostructural and cognitive impact of resistance exercise in Mild Cognitive Impairment (MCI). For the first time we show that hippocampal subareas particularly susceptible to volume loss in Alzheimer's disease (AD) are protected by resistance exercise for up to one year after training. One hundred MCI participants were randomised to one of four training groups: (1) Combined high intensity progressive resistance and computerised cognitive training (PRT +CCT), (2) PRT + Sham CCT, (3) CCT + Sham PRT, (4) Sham physical + sham cognitive training (SHAM + SHAM). Physical, neuropsychological and MRI assessments were carried out at baseline, 6 months (directly after training) and 18 months from baseline (12 months after intervention cessation). Here we report neuro-structural and functional changes over the 18-month trial period and the association with global cognitive and executive function measures. PRT but not CCT or PRT +CCT led to global long-term cognitive improvements above SHAM intervention at 18-month follow-up. Furthermore, hippocampal subfields susceptible to atrophy in AD were protected by PRT revealing an elimination of long-term atrophy in the left subiculum, and attenuation of atrophy in left CA1 and dentate gyrus when compared to SHAM + SHAM (p = 0.023, p = 0.020 and p = 0.027). These neuroprotective effects mediated a significant portion of long-term cognitive benefits. By contrast, within-training posterior cingulate plasticity decayed after training cessation and was unrelated to long term cognitive benefits. Neither general physical activity levels nor fitness change over the 18-month period mediated hippocampal trajectory, demonstrating that enduring hippocampal subfield plasticity is not a simple reflection of post-training changes in fitness or physical activity participation. Notably, resting-state fMRI analysis revealed that both the hippocampus and posterior cingulate participate in a functional network that continued to be upregulated following intervention cessation. Multiple structural mechanisms may contribute to the long-term global cognitive benefit of resistance exercise, developing along different time courses but functionally linked. For the first time we show that 6 months of high intensity resistance exercise is capable of not only promoting better cognition in those with MCI, but also protecting AD-vulnerable hippocampal subfields from degeneration for at least 12 months post-intervention. These findings emphasise the therapeutic potential of resistance exercise; however, future work will need to establish just how long-lived these outcomes are and whether they are sufficient to delay dementia.

Hypertension is a cardiovascular disease risk factor which can be modified by exercise. The effect of high intensity power training on ambulatory blood pressure (ABP) in older adults with type 2 diabetes (T2D) has never been studied. PURPOSE: To determine if high intensity power training (PRT) can reduce ABP in older adults with T2D. METHODS: One hundred three participants (51% male, 67.9 ±5.5 yrs, 100% T2D, 24hr SBP: 132 ± 13 mmHg, 24hr DBP: 73 ± 7 mmHg, 55% ABP hypertensive (141/83 mmHg)) were randomized into 3 times/week of PRT or low-intensity, non-progressive sham exercise (SHAM) for 12 months. Ambulatory blood pressure monitors were fitted to the non-dominant arm and worn continuously for 24 hours at baseline, 6- and 12-month timepoints. Sleep and waking times were logged by participants and used for analyses. Systolic (SBP) and diastolic (DBP) blood pressures during awake, asleep and overall 24-hr period were similar for both groups. RESULTS: There was no significant effect of time or group on any measure of ABP in older adults with T2D over 12 months. However, a fully adjusted model including baseline ABP hypertensive status (defined as baseline 24hr ABP of SBP > 130 or DBP > 80) revealed significant reductions in ABP domains over time in hypertensive vs. normotensive participants regardless of group assignment [mean difference (p-value): 24hr SBP, -4.1 vs 4.2 (p<0.01); 24hr DBP, -5.0 vs 0.9 (p<0.01); Awake SBP, -7.9 vs 5.8 (p<0.001); Awake DBP, -5.8 vs 1.3 (p<0.01); Sleep SBP, -3.5 vs 6.2 (p<0.05); Sleep DBP, -2.6 vs 2.5 (p=0.09)]. CONCLUSION: Overall, there was no change in ABP following 12 months of high or low intensity exercise training in older adults with T2D. However, in those with hypertension at baseline, both PRT and SHAM exercise were associated with clinically meaningful and significant reductions in ABP domains over 12 months. The mean difference of -8 mmHg in Awake SBP after 12 months of exercise in hypertensive individuals with T2D is particularly noteworthy. Extrapolating from meta-analyses of anti-hypertensive medication effects, a difference of this magnitude may be associated with major cardiovascular disease risk reduction.

ABSTRACTBackgroundIndividuals with Mild Cognitive Impairment (MCI) have more gait variability under dual-task conditions than cognitively healthy adults. However, characteristics associated with this susceptibility of gait to dual-task stress are unknown.MethodsTesting was performed at baseline in the Study of Mental And Resistance Training (SMART). Ninety-three adults with MCI (age 70±6.8 years; 66.6% female) performed a single- and dual-task walk (cognitive distractor=letter fluency), in random order. Linear and non-linear gait variability were measured using force-sensitive insoles. Cognitive performance during dual-tasking was assessed by the number of correct words vocalized. Cognitive function, brain Magnetic Resonance Imaging (MRI), muscle strength, aerobic capacity, body composition, physical and psychosocial function were also assessed as potential correlates of gait dynamics.ResultsGait dynamics worsened during dual-tasking, with decrements in both stride time variability (p<0.001) and detrended fluctuation analysis (DFA) (p=0.001). Lower aerobic capacity and thinner posterior cingulate cortex were associated with greater decrements in DFA (p<0.05). Smaller hippocampal volume, worse psychological well-being and poorer static balance were associated with greater decrements in stride time variability (p<0.05). By contrast, cognitive performance did not change under dual-task conditions compared to seated testing (p=0.13).ConclusionsUnder dual-task conditions, participants with MCI preserved their cognitive performance at the expense of gait stability. Decrements in dual-tasking gait were associated with lower aerobic fitness, balance, psychological well-being, and brain volume in cognitively-relevant areas of the posterior cingulate and hippocampus, all potentially modifiable characteristics. Trials of targeted interventions are needed to determine the potential plasticity of gait variability in high-risk cohorts.

Genome-wide association studies in obesity have identified a large number of non-coding loci located near genes expressed in the central nervous system. However, due to the difficulties in isolating and characterizing specific neuronal subpopulations, few obesity-associated single-nucleotide polymorphisms have been functionally characterized. Leptin-responsive neurons in the hypothalamus are essential in controlling energy homoeostasis and body weight. Here, we combine fluorescence-activated cell sorting of leptin-responsive hypothalamic neuron nuclei with genomic and epigenomic approaches (RNA sequencing, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing) to generate a comprehensive map of leptin response-specific regulatory elements, several of which overlap obesity-associated genome-wide association study variants. We demonstrate the usefulness of our leptin response neuron regulome, by functionally characterizing an enhancer near Socs3, a leptin response-associated transcription factor. We envision our data to serve as a useful resource and a blueprint for functionally characterizing obesity-associated single-nucleotide polymorphisms in the hypothalamus.

A wide range of human diseases result from haploinsufficiency, where the function of one of the two gene copies is lost. Here, we targeted the remaining functional copy of a haploinsufficient gene using CRISPR-mediated activation (CRISPRa) in Sim1 and Mc4r heterozygous mouse models to rescue their obesity phenotype. Transgenic-based CRISPRa targeting of the Sim1 promoter or its distant hypothalamic enhancer up-regulated its expression from the endogenous functional allele in a tissue-specific manner, rescuing the obesity phenotype in Sim1 heterozygous mice. To evaluate the therapeutic potential of CRISPRa, we injected CRISPRa-recombinant adeno-associated virus into the hypothalamus, which led to reversal of the obesity phenotype in Sim1 and Mc4r haploinsufficient mice. Our results suggest that endogenous gene up-regulation could be a potential strategy to treat altered gene dosage diseases.

Most monogenic cases of obesity in humans have been linked to mutations in genes encoding members of the leptin-melanocortin pathway. Specifically, mutations in MC4R, the melanocortin-4 receptor gene, account for 3-5% of all severe obesity cases in humans1-3. Recently, ADCY3 (adenylyl cyclase 3) gene mutations have been implicated in obesity4,5. ADCY3 localizes to the primary cilia of neurons 6 , organelles that function as hubs for select signaling pathways. Mutations that disrupt the functions of primary cilia cause ciliopathies, rare recessive pleiotropic diseases in which obesity is a cardinal manifestation 7 . We demonstrate that MC4R colocalizes with ADCY3 at the primary cilia of a subset of hypothalamic neurons, that obesity-associated MC4R mutations impair ciliary localization and that inhibition of adenylyl cyclase signaling at the primary cilia of these neurons increases body weight. These data suggest that impaired signaling from the primary cilia of MC4R neurons is a common pathway underlying genetic causes of obesity in humans.

Cognitive and physical exercise may reduce risk of dementia in mild cognitive impairment (MCI) but the underlying mechanisms are poorly understood. The SMART is a longitudinal randomised controlled trial that compares the benefits of isolated and combined progressive resistance and computerised cognitive training in MCI. Previously, we revealed therapeutically relevant structural and functional brain changes immediately after training cessation1, however, no effects were found on hippocampal structure. Here, for the first time, we investigate the ongoing impact of training on hippocampal anatomy 12-months after cessation using linear mixed effects (LME) models to account for imperfect timing and missing data. Eighty six community-dwelling participants aged ≥55 with MCI were randomised into 4 training groups; 1- Combined computerised cognitive and progressive resistance training (CT+PRT), 2- PRT and Sham CT (PRT), 3- Sham PRT and CT (CT), 4- Double Sham (DS). Training consisted of 2x1.5hours/week for 6-months. Cognitive and MRI assessments were carried out at baseline (BL), 6-months (F1) (directly after training) and 18-months (F2) from BL. Whole-brain T13DTFE MR images were automatically processed with the longitudinal FreeSurfer analysis pipeline. Longitudinal hippocampal volume was analysed with a freely available LME Matlab tool, modelled as % of BL volume. A linear time x group interaction was selected as the main contrast of interest in a comprehensive model controlling for covariates (sex, education, age). Five alternate hypotheses tested for group x time interactions between BL->F1 and BL->F1->F2 (Table 1). LME models showed significant differences in left (but not right) hippocampal atrophy rates for either training intervention compared to DS across the entire 18-month follow-up period. There were no differences in hippocampal trajectories between PRT or CT, nor between combined training and the DS. Meta-analysis in MCI and Alzheimer's confirm a faster rate of atrophy in the left hippocampus compared to the right2. Our findings of preserved left but not right hippocampal volume due to training may therefore have implications for combating neurodegeneration. Further work is needed to determine if such training-related benefits are linked to improved memory and cognitive outcomes long term. References: 1-C. Suo, et al. Molecular Psychiatry. 2016.21:1633–1642 2-F. Shi et al. Hippocampus. 2009. 19:1055–1064. Render of hippocampi from FreeSurfer segmentation (left). Lowess plot of left hippocampal volume as a percentage of ICV (right). The lowess plot shows predicted values of left hippocampal volume from LME model. Sliding window data fraction was set to 0.9.

Cognitive and physical exercise may reduce risk of dementia in mild cognitive impairment (MCI) but the underlying mechanisms are poorly understood. The SMART is a longitudinal randomised controlled trial that compares the benefits of isolated and combined progressive resistance and computerised cognitive training in MCI. Previously, we revealed therapeutically relevant structural and functional brain changes immediately after training cessation1, however, no effects were found on hippocampal structure. Here, for the first time, we investigate the ongoing impact of training on hippocampal anatomy 12-months after cessation using linear mixed effects (LME) models to account for imperfect timing and missing data. Eighty six community-dwelling participants aged ≥55 with MCI were randomised into 4 training groups; 1- Combined computerised cognitive and progressive resistance training (CT+PRT), 2- PRT and Sham CT (PRT), 3- Sham PRT and CT (CT), 4- Double Sham (DS). Training consisted of 2x1.5hours/week for 6-months. Cognitive and MRI assessments were carried out at baseline (BL), 6-months (F1) (directly after training) and 18-months (F2) from BL. Whole-brain T13DTFE MR images were automatically processed with the longitudinal FreeSurfer analysis pipeline. Longitudinal hippocampal volume was analysed with a freely available LME Matlab tool, modelled as % of BL volume. A linear time x group interaction was selected as the main contrast of interest in a comprehensive model controlling for covariates (sex, education, age). Five alternate hypotheses tested for group x time interactions between BL->F1 and BL->F1->F2 (Table1). LME models showed significant differences in left (but not right) hippocampal atrophy rates for either training intervention compared to DS across the entire 18-month follow-up period. There were no differences in hippocampal trajectories between PRT or CT, nor between combined training and the DS. Meta-analysis in MCI and Alzheimer's confirm a faster rate of atrophy in the left hippocampus compared to the right2. Our findings of preserved left but not right hippocampal volume due to training may therefore have implications for combating neurodegeneration. Further work is needed to determine if such training-related benefits are linked to improved memory and cognitive outcomes long term. References 1-C. Suo, et al. Molecular Psychiatry. 2016.21,1633–1642 2-F. Shi et al. Hippocampus, 2009. 19:1055–1064. Render of hippocampi from FreeSurfer segmentation (left). Lowess plot of left hippocampal volume as a percentage of ICV (right). The lowess plot shows predicted values of left hippocampal volume from LME model. Sliding window data fraction was set to 0.9.

ObjectivesTo determine whether improvements in aerobic capacity (VO2peak) and strength after progressive resistance training (PRT) mediate improvements in cognitive function.DesignRandomized, double-blind, double-sham, controlled trial.SettingUniversity research facility.ParticipantsCommunity-dwelling older adults (aged 55) with mild cognitive impairment (MCI) (N = 100).InterventionPRT and cognitive training (CT), 2 to 3 days per week for 6 months.MeasurementsAlzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog); global, executive, and memory domains; peak strength (1 repetition maximum); and VO2peak.ResultsPRT increased upper (standardized mean difference (SMD) = 0.69, 95% confidence interval = 0.47, 0.91), lower (SMD = 0.94, 95% CI = 0.69-1.20) and whole-body (SMD = 0.84, 95% CI = 0.62-1.05) strength and percentage change in VO2peak (8.0%, 95% CI = 2.2-13.8) significantly more than sham exercise. Higher strength scores, but not greater VO2peak, were significantly associated with improvements in cognition (P < .05). Greater lower body strength significantly mediated the effect of PRT on ADAS-Cog improvements (indirect effect: = -0.64, 95% CI = -1.38 to -0.004; direct effect: = -0.37, 95% CI = -1.51-0.78) and global domain (indirect effect: = 0.12, 95% CI = 0.02-0.22; direct effect: = -0.003, 95% CI = -0.17-0.16) but not for executive domain (indirect effect: = 0.11, 95% CI = -0.04-0.26; direct effect: = 0.03, 95% CI = -0.17-0.23).ConclusionHigh-intensity PRT results in significant improvements in cognitive function, muscle strength, and aerobic capacity in older adults with MCI. Strength gains, but not aerobic capacity changes, mediate the cognitive benefits of PRT. Future investigations are warranted to determine the physiological mechanisms linking strength gains and cognitive benefits.

Haploinsufficiency, having only one functional copy of a gene, leads to a wide range of human disease and has been associated with over 300 genes. Here, we tested whether CRISPR activation (CRISPRa) could rescue a haploinsufficient disease in vivo. Haploinsufficiency of Sim1, a transcription factor involved in the leptin pathway, results in severe obesity in humans and mice. CRISPRa targeting of either the Sim1 promoter or its ~270kb distant hypothalamic enhancer using transgenic mice, rescued the obesity phenotype in Sim1 heterozygous mice. Interestingly, despite using a ubiquitous promoter for CRISPRa, Sim1 was upregulated only in tissues where the promoter or enhancer are active, suggesting that cis-regulatory elements can determine CRISPRa tissue-specificity. To further relate this to therapy, we injected CRISPRa adeno associated virus into the hypothalamus, leading to reversal of the obesity phenotype. This therapeutic strategy could be used to rescue numerous diseases resulting from altered gene dosage.

Hypertension is a cardiovascular disease (CVD) risk factor modifiable by exercise. The chronic effect of high-intensity, high-velocity resistance training (Power Training; POWER) on ambulatory blood pressure (ABP) in older adults with type 2 diabetes (T2D) is unknown.