Reduction of Plasma BCAAs following Roux-en-Y Gastric Bypass Surgery Is Primarily Mediated by FGF21.

Type 2 diabetes (T2D) is a challenging health concern worldwide. A lifestyle intervention to treat T2D is difficult to adhere, and the effectiveness of approved medications such as metformin, thiazolidinediones (TZDs), and sulfonylureas are suboptimal. On the other hand, bariatric procedures such as Roux-en-Y gastric bypass (RYGB) are being recognized for their remarkable ability to achieve diabetes remission, although the underlying mechanism is not clear. Recent evidence points to branched-chain amino acids (BCAAs) as a potential contributor to glucose impairment and insulin resistance. RYGB has been shown to effectively lower plasma BCAAs in insulin-resistant or T2D patients that may help improve glycemic control, but the underlying mechanism for BCAA reduction is not understood. Hence, we attempted to explore the mechanism by which RYGB reduces BCAAs. To this end, we randomized diet-induced obese (DIO) mice into three groups that underwent either sham or RYGB surgery or food restriction to match the weight of RYGB mice. We also included regular chow-diet-fed healthy mice as an additional control group. Here, we show that compared to sham surgery, RYGB in DIO mice markedly lowered serum BCAAs most likely by rescuing BCAA breakdown in both liver and white adipose tissues. Importantly, the restored BCAA metabolism following RYGB was independent of caloric intake. Fasting insulin and HOMA-IR were decreased as expected, and serum valine was strongly associated with insulin resistance. While gut hormones such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are postulated to mediate various surgery-induced metabolic benefits, mice lacking these hormonal signals (GLP-1R/Y2R double KO) were still able to effectively lower plasma BCAAs and improve glucose tolerance, similar to mice with intact GLP-1 and PYY signaling. On the other hand, mice deficient in fibroblast growth factor 21 (FGF21), another candidate hormone implicated in enhanced glucoregulatory action following RYGB, failed to decrease plasma BCAAs and normalize hepatic BCAA degradation following surgery. This is the first study using an animal model to successfully recapitulate the RYGB-led reduction of circulating BCAAs observed in humans. Our findings unmasked a critical role of FGF21 in mediating the rescue of BCAA metabolism following surgery. It would be interesting to explore the possibility of whether RYGB-induced improvement in glucose homeostasis is partly through decreased BCAAs.

Goats diagnosed with neoplasia display variability in clinical presentations, treatments, and outcomes.

OBJECTIVE: To describe clinical presentation, treatment, and short- and long-term outcomes of goats diagnosed with neoplasia. ANIMALS: 46 goats with a definitive diagnosis of ≥ 1 neoplastic process admitted over a 15-year period. PROCEDURES: Medical records for all goats admitted to the Colorado State University Veterinary Teaching Hospital over a 15-year period were reviewed to identify animals diagnosed with neoplasia. Signalment, presenting complaint, duration of clinical signs, diagnostic testing, treatment, and short-term outcomes were recorded. When available, long-term follow-up data were collected via email or telephone interview with owners. RESULTS: 46 goats with 58 neoplasms were identified. The prevalence of neoplasia within the study population was 3.2%. The most commonly diagnosed neoplasms were squamous cell carcinoma, thymoma, and mammary carcinoma. The Saanen breed was the most common breed noted in the study population. Evidence of metastasis was found in 7% of the goats. Long-term follow-up was available in 5 goats with mammary neoplasia that underwent bilateral mastectomy. No evidence of mass regrowth or metastasis was noted in any of the goats 5 to 34 months postoperatively. CLINICAL RELEVANCE: Goats are increasingly treated as companion rather than strictly production animals, making it important for veterinarians to provide more evidence-based and advanced clinical care. This study provided a clinical overview of presentation, treatment, and outcome for goats diagnosed with neoplasia and highlighted the challenges associated with the wide variety of neoplastic processes affecting goats.

Branched-Chain Amino Acids Are Linked with Alzheimer's Disease-Related Pathology and Cognitive Deficits.

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder with a complex pathophysiology. Type 2 diabetes (T2D) is a strong risk factor for AD that shares similar abnormal features including metabolic dysregulation and brain pathology such as amyloid and/or Tau deposits. Emerging evidence suggests that circulating branched-chain amino acids (BCAAs) are associated with T2D. While excess BCAAs are shown to be harmful to neurons, its connection to AD is poorly understood. Here we show that individuals with AD have elevated circulating BCAAs and their metabolites compared to healthy individuals, and that a BCAA metabolite is correlated with the severity of dementia. APPSwe mouse model of AD also displayed higher plasma BCAAs compared to controls. In pursuit of understanding a potential causality, BCAA supplementation to HT-22 neurons was found to reduce genes critical for neuronal health while increasing phosphorylated Tau. Moreover, restricting BCAAs from diet delayed cognitive decline and lowered AD-related pathology in the cortex and hippocampus in APP/PS1 mice. BCAA restriction for two months was sufficient to correct glycemic control and increased/restored dopamine that were severely reduced in APP/PS1 controls. Treating 5xFAD mice that show early brain pathology with a BCAA-lowering compound recapitulated the beneficial effects of BCAA restriction on brain pathology and neurotransmitters including norepinephrine and serotonin. Collectively, this study reveals a positive association between circulating BCAAs and AD. Our findings suggest that BCAAs impair neuronal functions whereas BCAA-lowering alleviates AD-related pathology and cognitive decline, thus establishing a potential causal link between BCAAs and AD progression.

Neural Underpinnings of Obesity: The Role of Oxidative Stress and Inflammation in the Brain.

Obesity prevalence is increasing at an unprecedented rate throughout the world, and is a strong risk factor for metabolic, cardiovascular, and neurological/neurodegenerative disorders. While low-grade systemic inflammation triggered primarily by adipose tissue dysfunction is closely linked to obesity, inflammation is also observed in the brain or the central nervous system (CNS). Considering that the hypothalamus, a classical homeostatic center, and other higher cortical areas (e.g. prefrontal cortex, dorsal striatum, hippocampus, etc.) also actively participate in regulating energy homeostasis by engaging in inhibitory control, reward calculation, and memory retrieval, understanding the role of CNS oxidative stress and inflammation in obesity and their underlying mechanisms would greatly help develop novel therapeutic interventions to correct obesity and related comorbidities. Here we review accumulating evidence for the association between ER stress and mitochondrial dysfunction, the main culprits responsible for oxidative stress and inflammation in various brain regions, and energy imbalance that leads to the development of obesity. Potential beneficial effects of natural antioxidant and anti-inflammatory compounds on CNS health and obesity are also discussed.

Teaching Tip: The Development of an Interactive Computer-Based Training Program for Timely and Humane On-Farm Pig Euthanasia.

With extensive knowledge and training in the prevention, management, and treatment of disease conditions in animals, veterinarians play a critical role in ensuring good welfare on swine farms by training caretakers on the importance of timely euthanasia. To assist veterinarians and other industry professionals in training new and seasoned caretakers, an interactive computer-based training program was created. It consists of three modules, each containing five case studies, which cover three distinct production stages (breeding stock, piglets, and wean to grower-finisher pigs). Case study development was derived from five specific euthanasia criteria defined in the 2015 Common Swine Industry Audit, a nationally recognized auditing program used in the US. Case studies provide information regarding treatment history, clinical signs, and condition severity of the pig and prompt learners to make management decisions regarding pig treatment and care. Once a decision is made, feedback is provided so learners understand the appropriateness of their decision compared to current industry guidelines. In addition to training farm personnel, this program may also be a valuable resource if incorporated into veterinary, graduate, and continuing education curricula. This innovative tool represents the first interactive euthanasia-specific training program in the US swine industry and offers the potential to improve timely and humane on-farm pig euthanasia.