Browsing by Author "Shin, Andrew C. (TTU)"
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Item Evaluation of the Central Effects of Systemic Lentiviral-Mediated Leptin Delivery in Streptozotocin-Induced Diabetic Rats(2021) Clark, Kimberly A.; Shin, Andrew C. (TTU); Sirivelu, Madhu P.; MohanKumar, Ramya C.; Maddineni, Sreenivasa R.; Ramachandran, Ramesh; MohanKumar, Puliyur S.; MohanKumar, Sheba M.J.Type 1 diabetes (T1D) is characterized by hyperphagia, hyperglycemia and activation of the hypothalamic–pituitary–adrenal (HPA) axis. We have reported previously that daily leptin injections help to alleviate these symptoms. Therefore, we hypothesized that leptin gene therapy could help to normalize the neuroendocrine dysfunction seen in T1D. Adult male Sprague Dawley rats were injected i.v. with a lentiviral vector containing the leptin gene or green fluorescent protein. Ten days later, they were injected with the vehicle or streptozotocin (STZ). HPA function was assessed by measuring norepinephrine (NE) levels in the paraventricular nucleus (PVN) and serum corticosterone (CS). Treatment with the leptin lentiviral vector (Lepvv) increased leptin and insulin levels in non-diabetic rats, but not in diabetic animals. There was a significant reduction in blood glucose levels in diabetic rats due to Lepvv treatment. Both NE levels in the PVN and serum CS were reduced in diabetic rats treated with Lepvv. Results from this study provide evidence that leptin gene therapy in STZ-induced diabetic rats was able to partially normalize some of the neuroendocrine abnormalities, but studies with higher doses of the Lepvv are needed to develop this into a viable option for treating T1D.Item Immunometabolism, Micronutrients, and Bariatric Surgery: The Use of Transcriptomics and Microbiota-Targeted Therapies(2020) Galyean, Shannon (TTU); Sawant, Dhanashree (TTU); Shin, Andrew C. (TTU)Background. Obesity is associated with the gut microbiota and decreased micronutrient status. Bariatric surgery is a recommended therapy for obesity. It can positively affect the composition of the gut bacteria but also disrupt absorption of nutrients. Low levels of micronutrients can affect metabolic processes, like glycolysis, TCA cycle, and oxidative phosphorylation, that are associated with the immune system also known as immunometabolism. Methods. MEDLINE, PUBMED, and Google Scholar were searched. Articles involving gut microbiome, micronutrient deficiency, gut-targeted therapies, transcriptome analysis, micronutrient supplementation, and bariatric surgery were included. Results. Studies show that micronutrients play a pivotal role in the intestinal immune system and regulating immunometabolism. Research demonstrates that gut-targeting therapies may improve the microbiome health for bariatric surgery populations. There is limited research that examines the role of micronutrients in modulating the gut microbiota among the bariatric surgery population. Conclusions. Investigations are needed to understand the influence that micronutrient deficiencies have on the gut, particularly immunometabolism. Nutritional transcriptomics shows great potential in providing this type of analysis to develop gut-modulating therapies as well as more personalized nutrition recommendations for bariatric surgery patients.Item Neural Underpinnings of Obesity: The Role of Oxidative Stress and Inflammation in the Brain(2020) Mullins, Caitlyn (TTU); Gannaban, Ritchel B. (TTU); Khan, Md Shahjalal (TTU); Shah, Harsh (TTU); Siddik, Md (TTU); Hegde, Vijay (TTU); Reddy, P. Hemachandra (TTUHSC); Shin, Andrew C. (TTU)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.Item Personalized Nutrition for Management of Micronutrient Deficiency—Literature Review in Non-bariatric Populations and Possible Utility in Bariatric Cohort(2020) Galyean, Shannon (TTU); Sawant, Dhanashree (TTU); Shin, Andrew C. (TTU)Background: Bariatric surgery can effectively treat morbid obesity; however, micronutrient deficiencies are common despite recommendations for high-dose supplements. Genetic predisposition to deficiencies underscores necessary identification of high-risk candidates. Personalized nutrition (PN) can be a tool to manage these deficiencies. Methods: Medline, PubMed, and Google Scholar were searched. Articles involving genetic testing, micronutrient metabolism, and bariatric surgery were included. Results: Studies show associations between genetic variants and micronutrient metabolism. Research demonstrates genetic testing to be a predictor for outcomes among obesity and bariatric surgery populations. There is limited research in bariatric surgery and micronutrient genetic variants. Conclusion: Genotype-based PN is becoming feasible to provide an effective treatment of micronutrient deficiencies associated with bariatric surgery. The role of genomic technology in micronutrient recommendations needs further investigation.Item Recent Progress on Branched-Chain Amino Acids in Obesity, Diabetes, and Beyond(2019) Siddik, Md Abu; Shin, Andrew C. (TTU)Branched-chain amino acids (BCAAs) are essential amino acids that are not synthesized in our body; thus, they need to be obtained from food. They have shown to provide many physiological and metabolic benefits such as stimulation of pancreatic insulin secretion, milk production, adipogenesis, and enhanced immune function, among others, mainly mediated by mammalian target of rapamycin (mTOR) signaling pathway. After identified as a reliable marker of obesity and type 2 diabetes in recent years, an increasing number of studies have surfaced implicating BCAAs in the pathophysiology of other diseases such as cancers, cardiovascular diseases, and even neurodegenerative disorders like Alzheimer's disease. Here we discuss the most recent progress and review studies highlighting both correlational and potentially causative role of BCAAs in the development of these disorders. Although we are just beginning to understand the intricate relationships between BCAAs and some of the most prevalent chronic diseases, current findings raise a possibility that they are linked by a similar putative mechanism.Item Reducing endogenous insulin is linked with protection against hepatic steatosis in mice(2020) Akheruzzaman, Md (TTU); Hegde, Vijay (TTU); Shin, Andrew C. (TTU); Dhurandhar, Nikhil V. (TTU)Background: Obesity and type 2 diabetes (T2D) are closely associated with hepatic steatosis (HS), which if untreated can advance to serious liver conditions. Since insulin promotes hepatic lipogenesis, reducing hyperinsulinemia may help in treating HS. E4orf1 is an adenovirus-derived protein that improves glucose clearance independent of insulin, lowers insulin amount required for glucose disposal, and reduces HS. As a next step, we evaluated the mechanism for E4orf1-induced reduction in HS and tested that E4orf1 does not induce hypoglycemia, an important attribute for its application as a potential anti-diabetic agent. Methods: C57Bl/6J mice that transgenically express E4orf1 in adipose tissue (E4orf-Tg) and wild-type (WT) mice received a chow diet for 6 weeks, followed by a high-fat (HF) diet for additional 10 weeks. Body composition, blood glucose, and serum insulin levels upon glucose load were measured at 0, 6, 7, and 16 weeks. Serum free fatty acid (FFA), triglyceride (TG), and hepatic TG were measured at study termination. We compared histology and the mRNA/protein markers of hepatic and adipose tissue lipid metabolism between the two groups of mice. Results: On chow diet, both groups remained normoglycemic, but E4orf1 expression reduced insulin response. On HF diet, glycemic control in WT deteriorated, whereas E4orf1 significantly enhanced glycemic control, lowered insulin response, reduced hepatic triglycerides, and serum FFA. Overall, a comparison of hepatic mRNA and/or protein expression suggested that E4orf1 expression significantly decreased de novo lipogenesis (DNL) and intracellular lipid transport and increased fat oxidation and TG export. Adipose tissue mRNA and protein markers suggested that E4orf1 expression lowered DNL and increased lipolysis. Conclusion: Considering that E4orf1 is not secreted in circulation, we postulate that reduced endogenous insulin in E4orf1 mice indirectly contributes to reduce HS by altering hepatic lipid metabolism, including lipogenesis. This study underscores the possibility of indirectly impacting HS by manipulating adipose tissue metabolism.Item Reduction of Plasma BCAAs following Roux-en-Y Gastric Bypass Surgery Is Primarily Mediated by FGF21(2023) Shah, Harsh (TTU); Kramer, Alyssa (TTU); Mullins, Caitlyn A. (TTU); Mattern, Marie (TTU); Gannaban, Ritchel B. (TTU); Townsend, R. Leigh; Campagna, Shawn R.; Morrison, Christopher D.; Berthoud, Hans Rudolf; Shin, Andrew C. (TTU)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.Item Responsiveness of hypothalamo-pituitary-adrenal axis to leptin is impaired in diet-induced obese rats(2019) Shin, Andrew C. (TTU); MohanKumar, Sheba M.J.; Balasubramanian, Priya; Sirivelu, Madhu P.; Linning, Katrina; Woolcock, Andrew; James, Michelle; MohanKumar, Puliyur S.Background/objectives: Diet-induced obese (DIO) rats have altered stress (HPA) axis activity compared to diet-resistant (DR) rats when chronically exposed to a high-fat (HF) diet. Since stress axis is tightly regulated by leptin, an adipocyte-secreted hormone that is important for controlling body weight, we hypothesized that leptin action is impaired in DIO rats leading to alterations in HPA axis activity. Subjects/methods: We intraperitoneally injected selectively bred DIO and DR rats with either saline or recombinant rat leptin. HPA axis activity was assessed by measuring norepinephrine (NE) in the paraventricular nucleus (PVN), corticotropin-releasing hormone (CRH) in the median eminence, and serum corticosterone (CORT). To test if HF exposure duration and the corresponding increase in leptin differentially affects HPA axis activity, we placed animals on a chow or HF diet for 1 or 6 weeks. Results: Leptin injection significantly increased serum leptin levels in both DIO and DR animals. It also reduced PVN NE in both groups, indicating that noradrenergic neurons in both groups remain responsive to leptin. HF diet duration-dependently increased serum leptin only in DIO animals whereas PVN NE increased in both groups. While DR rats responded to HF diet by increasing CRH and CORT at both time-points, responses in DIO rats varied, suggesting that they have altered HPA axis activity that may be dependent on HF-induced leptin levels and/or signaling. To understand the underlying mechanisms, we measured pSTAT-3, a marker of leptin signaling, in brainstem noradrenergic neurons and found reduced pSTAT-3 in A1 region of HF-fed DIO rats. We also found higher serum free fatty acids (FFAs) and a pro-inflammatory cytokine, IL-1β. Conclusions: Collectively, these findings reveal that DIO rats have inherent neuroendocrine impairment in NE-HPA axis circuitry that worsens with the extent of HF diet exposure, possibly due to brainstem leptin resistance and/or elevated circulating FFAs and IL-1β.Item Revisiting the Role of Vitamins and Minerals in Alzheimer’s Disease(2023) Shah, Harsh (TTU); Dehghani, Fereshteh (TTU); Ramezan, Marjan (TTU); Gannaban, Ritchel B. (TTU); Haque, Zobayda Farzana (TTU); Rahimi, Fatemeh; Abbasi, Soheil; Shin, Andrew C. (TTU)Alzheimer’s disease (AD) is the most common type of dementia that affects millions of individuals worldwide. It is an irreversible neurodegenerative disorder that is characterized by memory loss, impaired learning and thinking, and difficulty in performing regular daily activities. Despite nearly two decades of collective efforts to develop novel medications that can prevent or halt the disease progression, we remain faced with only a few options with limited effectiveness. There has been a recent growth of interest in the role of nutrition in brain health as we begin to gain a better understanding of what and how nutrients affect hormonal and neural actions that not only can lead to typical cardiovascular or metabolic diseases but also an array of neurological and psychiatric disorders. Vitamins and minerals, also known as micronutrients, are elements that are indispensable for functions including nutrient metabolism, immune surveillance, cell development, neurotransmission, and antioxidant and anti-inflammatory properties. In this review, we provide an overview on some of the most common vitamins and minerals and discuss what current studies have revealed on the link between these essential micronutrients and cognitive performance or AD.Item White and brown adipose tissue functionality is impaired by fine particulate matter (PM2.5) exposure(2022) Della Guardia, Lucio; Shin, Andrew C. (TTU)Chronic exposure to high levels of particulate matter (PM) is correlated to a higher prevalence of cardio-metabolic disturbances. Adipose tissue represents a pivotal regulator of metabolic homeostasis, and its dysfunction is associated with health issues in PM-exposed models. This review discusses the adaptive changes of white (WAT) and brown (BAT) adipose tissue in response to fine particulate matter (PM2.5), investigating the underlying pathophysiology. In exposed models, PM2.5 increases oxidative stress and impairs mitochondria functionality and biogenesis in WAT and BAT. Chronic exposure also upregulates the main apoptotic/pro-inflammatory pathways and promotes the infiltration of monocytes and the accumulation of activated macrophages. Oxidative stress and inflammation are responsible for the inhibition of insulin signal transduction and glucose uptake in both the adipose tissues. The increased inflammatory status also suppresses the metabolic activity of brown adipocytes, promoting the whitening. Altogether, this evidence suggests the shift of WAT and BAT toward an inflammatory and metabolic dysfunctional phenotype. Although the underlying mechanisms remain to be clarified, the development of inflammation in lungs, gut, and hypothalamus seems to have a pivotal role in the alteration of adipose tissue homeostasis. The potential consequences on systemic cardio-metabolic health render the relationship PM-adipose tissue a key issue to investigate.