David Andrew Harris

Obesity and diabetes are well‐established risk factors for Alzheimer's disease (AD), implicating metabolic dysfunction in AD pathogenesis. Sleeve gastrectomy (SG) is among the most effective metabolic interventions available, yet its impact on AD progression remains poorly understood. We hypothesized that SG performed early in life would improve metabolic health, attenuate AD pathology, and preserve cognition in a transgenic AD mouse model. Five‐week‐old female 3xTg‐AD mice were preconditioned on a Western diet (WD) to induce obesity and glucose intolerance, then randomized to SG or sham surgery and maintained on either Control or continued WD for 12 months. Metabolic phenotyping, body composition, and cognitive assessments (Novel Object Recognition, Barnes Maze, Fear Conditioning) were performed longitudinally, with histological and molecular brain analysis at endpoint. Under Control‐fed conditions, SG reduced fat mass and improved peripheral insulin sensitivity independent of food intake. These changes were accompanied by reduced cortical Aβ plaque burden and attenuated astrocytic (GFAP) and microglial (IBA1) activation, specifically in the cortex. Mechanistically, SG altered the insulin signaling‐autophagy axis in a region‐specific manner, with increased pAKT and suppressed ATG5/ATG7/ATG16L1 in the cortex. Under persistent WD, SG improved glucose homeostasis, reduced fat mass, lowered frailty, and rescued short‐ and long‐term spatial memory deficits in the Barnes maze, accompanied by reduced cortical Aβ burden. Collectively, these findings provide the first preclinical evidence that SG attenuates AD progression through a brain insulin signaling‐autophagy axis, supporting metabolic surgery as a promising disease‐modifying intervention for AD prevention in individuals with obesity.

Background: Prevalence of same day bariatric surgery programs is rising. While observational studies suggest same day outcomes are similar to inpatient programs, the ability to detect early post-operative bleeding in same day patients is uncertain. We compared hemoglobin values between patients who did or did not develop post-operative bleeding to delineate when hemoglobin trends diverge. Methods: Patients who underwent sleeve gastrectomy or gastric bypass at a single center from 2020 to 2024 were stratified into those who did or did not develop bleeding that required transfusion and/or surgical or endoscopic intervention. Three standardized hemoglobin draws (pre-operative, four-hour post-operative, morning of post-operative day 1) were compared between groups. Time to the first clinical sign of bleeding and intervention were evaluated for patients who developed clinically significant bleeding. Results: 1,457 patients were included (mean [SD] age 45.4 [10.8] years; 85.5% White; 82.0% female, 60.6% sleeve gastrectomy). Thirty-nine patients (2.7%) developed bleeding. Mean pre-operative and four-hour post-operative hemoglobin values were similar. Hemoglobin values on the morning of post-operative day 1 were significantly lower for the patients who bled [10.7 g/dL (SD 1.6) vs. 12.5 g/dL (1.1); p < 0.001]. The median time to the first clinical sign of bleeding was 9 h (IQR 6.25–17.5). The median time to intervention was 23 h (17–32). Conclusion: Hemoglobin trends remained similar between groups until the morning of postoperative day 1. Clinical signs of bleeding did not develop until after the typical same day surgery observation period for most patients. These findings suggest that patients who develop clinically significant bleeding after same day bariatric surgery may not be identifiable prior to discharge and that next day discharge is a safer alternative. Key Points: • Post-operative hemoglobin values after bariatric surgery were compared between patients who did or did not develop post-operative bleeding. • Hemoglobin values were similar until the morning of post-operative day 1. • The first clinical signs of bleeding developed at a median of 9 h after surgery. • Some patients who develop clinically significant bleeding after same day bariatric surgery may not be identified prior to discharge.

Obesity and diabetes are well-established risk factors for Alzheimer’s disease (AD), implicating metabolic dysfunction in AD pathogenesis. Sleeve gastrectomy (SG) is among the most effective metabolic interventions available, yet its impact on AD progression remains poorly understood. We hypothesized that SG performed early in life would improve metabolic health, attenuate AD pathology, and preserve cognition in a transgenic AD mouse model. Five-week-old female 3xTg-AD mice were preconditioned on a Western diet (WD) to induce obesity and glucose intolerance, then randomized to SG or sham surgery and maintained on either standard chow or continued WD for 12 months. Metabolic phenotyping, body composition, and cognitive assessments (Novel Object Recognition, Barnes Maze, Fear Conditioning) were performed longitudinally, with histological and molecular analysis of brain tissue at endpoint. Under chow-fed conditions, SG reduced adiposity, improved insulin sensitivity, and decreased cortical Aβ plaque burden, accompanied by attenuated gliosis (GFAP, IBA1) and region-specific, insulin pathway-dependent modulation of autophagy. Under persistent WD, SG improved metabolic health, frailty, spatial cognition, and Aβ pathology, again with corresponding perturbations in autophagy pathway activity. Across all groups, food intake did not differ significantly, indicating that these effects were not secondary to caloric restriction. Collectively, these data suggest that SG engages neuroprotective brain insulin signaling pathways, supporting metabolic surgery as a promising disease-modifying intervention for AD prevention in individuals with obesity.

Folates participate in the one-carbon metabolism (OCM) cycle, supporting many biochemical pathways. Existing methods to profile folate are limited in the diversity of vitamers they measure and the samples they profile. Here we present a metabolomics workflow for stable extraction, separation and measurement of folates, along with precursors and products of OCM-associated pathways. We profile these metabolites in 37 mouse tissues to chart an interactive 'OCM atlas' ( https://chaudharilab.com/folate-atlas/ ), revealing vast heterogeneity across organs and an uncharacterized folate derivative. We discover that, in adult mice, the gut microbiota is a consumer of folate and folate polyglutamylation in the host is not regulated by folate availability. Germ-free mice show tissue-specific shifts in methyl donor abundances relative to conventionally raised mice, indicative of altered DNA methylation. Correlation analyses uncover the central roles of folates in potentially modulating other biochemical pathways in tissues, thus linking microbial folate consumption directly to its global impacts on host metabolism.

Agonists of the G protein-coupled receptor TGR5 have long been sought-after for their metabolic benefits. Intestinal TGR5 activation induces secretion of the antidiabetic hormone GLP-1, which can systemically improve diabetes phenotypes in multiple organs. However, no TGR5 agonist drug candidate has succeeded in clinical trials due to their low potency and unwanted side effects. A challenge in the field has been the development of TGR5 agonists that are non-toxic, long-acting, and have functional selectivity for G protein-biased agonism. In this study, we propose a systematic pipeline for engineering optimal TGR5 agonists with antidiabetic properties. This pipeline is interdisciplinary, combining in silico, in vitro, and in vivo assays to design and validate drug candidates. We identify 2 lead compounds that outline the necessary beneficial properties for a successful TGR5 agonist against diabetes. We uncover the molecular mechanisms that allow TGR5 agonists to induce the transcription of their target, TGR5, in intestinal enteroendocrine cells. Lastly, we investigate the molecular interactions of our lead candidates in the TGR5 binding pocket to identify optimal parameters for stability and biological activity. Our strategy for TGR5 agonist design and evaluation has the potential to guide the discovery process for targeted TGR5 therapeutics for metabolic diseases.

Background: Obesity and metabolic disease drive premature aging and reduced lifespan. While metabolic interventions like calorie restriction, protein restriction, and time restricted feeding have been shown to improved lifespan, they are either not effective or sustainable for most humans. Bariatric surgery is the most efficacious metabolic intervention available and is associated with increased lifespan. However, whether its longevity benefits derive solely from weight reduction or reflect surgery-specific metabolic reprogramming remains unknown. Methods: We employed a lean mouse model of sleeve gastrectomy (SG) in which young, lean male C57BL/6J mice underwent SG or sham operation while maintained on low-fat chow, then were challenged with high-fat diet (HFD) in midlife. We assessed glucose metabolism, body composition, energy expenditure, hepatic histology, adipose tissue inflammation, and cecal microbiome composition. Results: Despite identical weight and food intake on low-fat chow, SG mice demonstrated improved glucose tolerance and insulin sensitivity prior to HFD challenge. Upon HFD exposure, SG animals exhibited enhanced metabolic flexibility with greater capacity for fat oxidation, increased energy expenditure, attenuated weight gain, and reduced adiposity compared to sham controls. SG further reduced hepatic lipid accumulation and attenuated visceral adipose tissue inflammation, marked by decreased pro-inflammatory cytokine expression and reduced macrophage infiltration. These metabolic benefits occurred independently of caloric intake. Cecal microbiome profiling revealed surgery-specific remodeling characterized by Lactobacillus enrichment and reductions in Verrucomicrobia and Clostridia — a pattern distinct from caloric restriction and consistent with prior SG studies. Conclusions: Early-life SG confers durable, weight-loss-independent protection against midlife metabolic deterioration. Gut microbiome remodeling, particularly enrichment of Lactobacillus species, represents a candidate mediating mechanism and a potential therapeutic target for aging and metabolic disease.

Objective: Alexander disease (AxD) is a severe neurodegenerative disorder caused by gain‐of‐function mutations in the gene for GFAP, which lead to protein aggregation and a primary astrocytopathy. Symptoms vary, but failure to thrive (FTT) and frequent emesis are common and cause significant morbidity. Here we investigate GDF15, a member of the TGFβ superfamily, which regulates energy balance and appetite, as a potential mediator of FTT in AxD. Methods: In this study, we use the Gfap ^+/R237H rat model (R237H), in which pups fail to gain weight after weaning and become frail and impaired as they mature, to assess muscle atrophy, energy expenditure, and feeding behavior in AxD. We measure GDF15 in brain and cerebrospinal fluid (CSF), assess activation of its receptor GFRAL in area postrema neurons, and use GFAP suppression to correlate FTT phenotypes with GDF15 expression. Finally, we measure GDF15 in patients with AxD. Results: R237H rats show reduced lean and fat mass and muscle atrophy despite reduced energy expenditure, and at an early age exhibit pica and anorexia. GDF15 is expressed by R237H rat astrocytes and is elevated in brainstem and CSF, but not in plasma. Neurons expressing GFRAL, a mediator of GDF15‐induced appetite suppression, are activated in the area postrema. Suppression of GFAP using antisense oligonucleotides normalizes weight gain and GDF15 levels in brainstem and CSF. In human AxD, GDF15 is elevated in CSF, but not in blood. Interpretation: GDF15 is associated with FTT in AxD and provides both a target and useful biomarker for the development of future therapeutics.

Caloric restriction slows or prevents Alzheimer's disease in animal models. Calorie restriction is typically implemented in rodents through feeding once per day; as the animals quickly consume their food, they are subject to a prolonged self-imposed fasting period between meals. Here, we examine the distinct contributions of fasting and reduced calories to the beneficial effects of calorie restriction on Alzheimer's disease by placing male and female 3xTg and non-transgenic control mice on a series of diet regimens enabling us to dissect the effects of calories and fasting. We find that reducing calories alone improves body weight and glucose tolerance. However, a prolonged fast between meals is necessary for many of the benefits of calorie restriction, including improved insulin sensitivity, reduced Alzheimer's pathology, improved neuroprotective signaling, and improved cognition. Overall, our results suggest that both when and how much we eat may influence the development and progression of Alzheimer's disease.