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Tavakkoli, Ali

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Tavakkoli

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Ali

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Tavakkoli, Ali
Author's Publications: search.filters.isAuthorOfPublication.84614211-ab19-443f-b999-0317a7f59f23

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    Phosphorylation of Beta-3 adrenergic receptor at serine 247 by ERK MAP kinase drives lipolysis in obese adipocytes
    (Elsevier, 2018) Hong, Shangyu; Song, Wei; Zushin, Peter-James H.; Liu, Bingyang; Jedrychowski, Mark; Mina, Amir I.; Deng, Zhaoming; Cabarkapa, Dimitrije; Hall, Jessica; Palmer, Colin J.; Aliakbarian, Hassan; Szpyt, John; Gygi, Steven; Tavakkoli, Ali; Lynch, Lydia; Perrimon, Norbert; Banks, Alexander
    Objective: The inappropriate release of free fatty acids from obese adipose tissue stores has detrimental effects on metabolism, but key molecular mechanisms controlling FFA release from adipocytes remain undefined. Although obesity promotes systemic inflammation, we find activation of the inflammation-associated Mitogen Activated Protein kinase ERK occurs specifically in adipose tissues of obese mice, and provide evidence that adipocyte ERK activation may explain exaggerated adipose tissue lipolysis observed in obesity. Methods and Results: We provide genetic and pharmacological evidence that inhibition of the MEK/ERK pathway in human adipose tissue, mice, and flies all effectively limit adipocyte lipolysis. In complementary findings, we show that genetic and obesity-mediated activation of ERK enhances lipolysis, whereas adipose tissue specific knock-out of ERK2, the exclusive ERK1/2 protein in adipocytes, dramatically impairs lipolysis in explanted mouse adipose tissue. In addition, acute inhibition of MEK/ERK signaling also decreases lipolysis in adipose tissue and improves insulin sensitivity in obese mice. Mice with decreased rates of adipose tissue lipolysis in vivo caused by either MEK or ATGL pharmacological inhibition were unable to liberate sufficient White Adipose Tissue (WAT) energy stores to fuel thermogenesis from brown fat during a cold temperature challenge. To identify a molecular mechanism controlling these actions, we performed unbiased phosphoproteomic analysis of obese adipose tissue at different time points following acute pharmacological MEK/ERK inhibition. MEK/ERK inhibition decreased levels of adrenergic signaling and caused de-phosphorylation of the β3-adrenergic receptor (β3AR) on serine 247. To define the functional implications of this phosphorylation, we showed that CRISPR/Cas9 engineered cells expressing wild type β3AR exhibited β3AR phosphorylation by ERK2 and enhanced lipolysis, but this was not seen when serine 247 of β3AR was mutated to alanine. Conclusion: Taken together, these data suggest that ERK activation in adipocytes and subsequent phosphorylation of the β3AR on S247 are critical regulatory steps in the enhanced adipocyte lipolysis of obesity.
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    Effect of Portal Glucose Sensing on Systemic Glucose Levels in SD and ZDF Rats
    (Public Library of Science, 2016) Pal, Atanu; Rhoads, David; Tavakkoli, Ali
    Background: The global epidemic of Type-2-Diabetes (T2D) highlights the need for novel therapeutic targets and agents. Roux-en-Y-Gastric-Bypass (RYGB) is the most effective treatment. Studies investigating the mechanisms of RYGB suggest a role for post-operative changes in portal glucose levels. We investigate the impact of stimulating portal glucose sensors on systemic glucose levels in health and T2D, and evaluated the role of sodium-glucose-cotransporter-3 (SGLT3) as the possible sensor. Methods: Systemic glucose and hormone responses to portal stimulation were measured. In Sprague-Dawley (SD) rats, post-prandial state was simulated by infusing glucose into the portal vein. The SGLT3 agonist, alpha-methyl-glucopyranoside (αMG), was then added to further stimulate the portal sensor. To elucidate the neural pathway, vagotomy or portal denervation was followed by αMG+glucose co-infusion. The therapeutic potential of portal glucose sensor stimulation was investigated by αMG-only infusion (vs. saline) in SD and Zucker-Diabetic-Fatty (ZDF) rats. Hepatic mRNA expression was also measured. Results: αMG+glucose co-infusion reduced peak systemic glucose (vs. glucose alone), and lowered hepatic G6Pase expression. Portal denervation, but not vagotomy, abolished this effect. αMG-only infusion lowered systemic glucose levels. This glucose-lowering effect was more pronounced in ZDF rats, where portal αMG infusion increased insulin, C-peptide and GIP levels compared to saline infusions. Conclusions: The portal vein is capable of sensing its glucose levels, and responds by altering hepatic glucose handling. The enhanced effect in T2D, mediated through increased GIP and insulin, highlights a therapeutic target that could be amenable to pharmacological modulation or minimally-invasive surgery.
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    Distal Pancreatic Resection for Neuroendocrine Tumors: Is Laparoscopic Really Better than Open?
    (Springer US, 2015) Xourafas, Dimitrios; Tavakkoli, Ali; Clancy, Thomas; Ashley, Stanley
    Background: The latest studies on surgical and cost-analysis outcomes after laparoscopic distal pancreatectomy (LDP) highlight mixed and insufficient results. Whereas several investigators have compared surgical outcomes of LDP vs. open distal pancreatectomy (ODP) for adenocarcinomas, few similar studies have focused on pancreatic neuroendocrine tumors (PNETs). Methods: We reviewed the medical records of PNET patients undergoing distal pancreatectomy between 2004 and 2014. Patients were divided into LDP vs. ODP groups. Demographics, relevant comorbidities, oncologic variables, and cost-analysis data were assessed. Survival and Cox proportional hazards analyses were used to evaluate outcomes. Results: Of the 171 distal pancreatectomies for PNETs, 73 were laparoscopic, whereas 98 were open. Patients undergoing LDP demonstrated significantly lower rates of postoperative complications (P = 0.028) and had significantly shorter hospital stays (P = 0.008). On multivariable analysis, positive resection margins (P = 0.046), G3 grade (P = 0.036), advanced WHO classification (P = 0.016), TNM stage (P = 0.018), and readmission (P = 0.019) were significantly associated with poor survival; however, method of resection (LDP vs. ODP) was not (P = 0.254). The median total direct costs of LDP vs. ODP did not differ significantly. Conclusions: In response to the recent considerable controversy surrounding the costs and surgical outcomes of LDP vs. ODP, our results show that LDP for PNETs is cost-neutral and significantly reduces postoperative morbidity without compromising oncologic outcomes and survival.
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    Effect of Roux-en-Y Gastric Bypass Surgery on Bile Acid Metabolism in Normal and Obese Diabetic Rats
    (Public Library of Science, 2015) Bhutta, Hina Y; Rajpal, Neetu; White, Wendy; Freudenberg, Johannes M.; Liu, Yaping; Way, James; Rajpal, Deepak; Cooper, David C.; Young, Andrew; Tavakkoli, Ali; Chen, Lihong
    In addition to classic functions of facilitating hepatobiliary secretion and intestinal absorption of lipophilic nutrients, bile acids (BA) are also endocrine factors and regulate glucose and lipid metabolism. Recent data indicate that antiobesity bariatric procedures e.g. Roux-en-Y gastric bypass surgery (RYGB), which also remit diabetes, increase plasma BAs in humans, leading to the hypothesis that BAs may play a role in diabetes resolution following surgery. To investigate the effect of RYGB on BA physiology and its relationship with glucose homeostasis, we undertook RYGB and SHAM surgery in Zucker diabetic fatty (ZDF) and normoglycemic Sprague Dawley (SD) rats and measured plasma and fecal BA levels, as well as plasma glucose, insulin, Glucagon like peptide 1 (GLP-1) and Peptide YY (PYY), 2 days before and 3, 7, 14 and 28 days after surgery. RYGB decreased body weight and increased plasma GLP-1 in both SD and ZDF rats while decreasing plasma insulin and glucose in ZDF rats starting from the first week. Compared to SHAM groups, both SD-RYGB and ZDF-RYGB groups started to have increases in plasma total BAs in the second week, which might not contribute to early post-surgery metabolic changes. While there was no significant difference in fecal BA excretion between SD-RYGB and SD-SHAM groups, the ZDF-RYGB group had a transient 4.2-fold increase (P<0.001) in 24-hour fecal BA excretion on post-operative day 3 compared to ZDF-SHAM, which paralleled a significant increase in plasma PYY. Ratios of plasma and fecal cholic acid/chenodeoxycholic acid derived BAs were decreased in RYGB groups. In addition, tissue mRNA expression analysis suggested early intestinal BA reabsorption and potentially reduced hepatic cholic acid production in RYGB groups. In summary, we present novel data on RYGB-mediated changes in BA metabolism to further understand the role of BAs in RYGB-induced metabolic effects in humans.