Small Molecular Allosteric Activator of the Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA) Attenuates Diabetes and Metabolic Disorders

Abstract

Dysregulation of endoplasmic reticulum (ER) Ca2؉ homeostasis triggers ER stress leading to the development of insulin resistance in obesity and diabetes. Impaired function of the sarco/endoplasmic reticulum Ca 2؉ -ATPase (SERCA) has emerged as a major contributor to ER stress. We pharmacologically activated SERCA2b in a genetic model of insulin resistance and type 2 diabetes (ob/ob mice) with a novel allosteric activator, CDN1163, which markedly lowered fasting blood glucose, improved glucose tolerance, and ameliorated hepatosteatosis but did not alter glucose levels or body weight in lean controls. Importantly, CDN1163-treated ob/ob mice maintained euglycemia comparable with that of lean mice for >6 weeks after cessation of CDN1163 administration. CDN1163-treated ob/ob mice showed a significant reduction in adipose tissue weight with no change in lean mass, assessed by magnetic resonance imaging. They also showed an increase in energy expenditure using indirect calorimetry, which was accompanied by increased expression of uncoupling protein 1 (UCP1) and UCP3 in brown adipose tissue. CDN1163 treatment significantly reduced the hepatic expression of genes involved in gluconeogenesis and lipogenesis, attenuated ER stress response and ER stress-induced apoptosis, and improved mitochondrial biogenesis, possibly through SERCA2-mediated activation of AMP-activated protein kinase pathway. The findings suggest that SERCA2b activation may hold promise as an effective therapy for type-2 diabetes and metabolic dysfunction.Obesity and insulin resistance are major causes of type 2 diabetes (T2D), 2 which represents an enormous health burden to societies worldwide. T2D is now one of the most prevalent diseases globally and is the fourth leading cause of death in many developed countries (1). Endoplasmic reticulum stress (ER stress) has emerged as an important cause of the metabolic syndrome and T2D. ER stress and the unfolded protein response have now been described in organs playing key roles in metabolic homeostasis such as liver, pancreatic ␤-cells, adipose tissue, and hypothalamus in both obese and/or diabetic humans and rodents (2-5) and have recently emerged as key pathophysiological pathways triggering insulin resistance and T2D (4). Amelioration of ER stress through chemical chaperones has been demonstrated to be a promising pharmacological strategy for treatment of T2D (6 -10). The ER is the main storage site of intracellular Ca 2ϩ , and alterations in Ca 2ϩ homeostasis have been demonstrated to trigger ER stress and activation of the unfolded protein response (11, 12). The sarco/endoplasmic reticulum Ca 2ϩ -ATPase (SERCA) pumps Ca 2ϩ from the cytoplasm into the ER. Recent studies demonstrate that SERCA dysfunction leads to elevation of cytoplasmic calcium and triggers ER stress. SERCA2 activity and expression is diminished in islets (13), liver (2, 14), and heart (15) in animal models of obesity/ diabetes, highlighting a potential pathological role for SERCA2 dysfunction and disturbed ER Ca 2ϩ homeostasis in the dev...

SERCA2 Deficiency Impairs Pancreatic β-Cell Function in Response to Diet-Induced Obesity

“…Although tissue-specific deletion models are needed to fully resolve the effects of SERCA2 loss on β-cell function and peripheral insulin sensitivity, our data and those of others suggest that strategies aimed at restoration of SERCA2 expression and/or modulation of SERCA2 activity represent viable strategies to improve glucose homeostasis (24,28,30). Finally, these data also have relevance for humans with Darier-White disease, in which one copy of the ATP2A2 gene is defective.…”

“…Previous in vitro experiments have also shown that SERCA2 and SERCA1 interact with insulin receptor substrate 1 and 2 in skeletal muscle in an insulin-dependent manner, suggesting an effect of SERCA activity on glucose uptake (29). Furthermore, in vivo adenoviral-mediated restoration of SERCA2b expression in the liver improved glucose homeostasis in obese mice (24,28), whereas treatment with the SERCA activator CDN1163 improved hepatic ER stress and glucose tolerance in the ob / ob mouse model (30). In our study, however, S2HET and control mice exhibited indistinguishable patterns of weight gain, body composition, and systemic and tissue-specific insulin sensitivity, suggesting that the glucose intolerance observed in the HFD-fed S2HET mice did not arise from perturbations in adiposity or insulin sensitivity.…”

Adipose tissue inflammation: a cause or consequence of obesity-related insulin resistance?

“…ER stress might also integrate signals derived from enlarged adipocytes, which release higher amounts of FFAs [69]. Administration of chaperons or small molecules which decrease ER stress has been shown to reduce adipose tissue inflammation, improve insulin sensitivity and metabolic disorders [70,71]. Therefore, targeting adipose tissue stress and reversing adipose tissue inflammation and its related metabolic abnormalities may hold promise as a future therapeutic strategy in the treatment of type 2 diabetes.…”

Tumor suppressive Ca2+ signaling is driven by IP3 receptor fitness

“…In wild-type p53 tumors, direct p53 activators might be of use. Other solace may come from SERCA-activating small molecules like CDN1163 [54], provided these agents can be delivered to tumor cells while sparing healthy cells [52].…”

“…In wild-type p53 tumors, direct p53 activators might be of use. Other solace may come from SERCA-activating small molecules like CDN1163 [54], provided these agents can be delivered to tumor cells while sparing healthy cells [52].These recent papers highlight that deregulation of IP 3 R3 ubiquitination homeostasis not only impacts death and survival of cells but also contributes to the oncogenic behavior of cells with dysfunctional tumor suppressors by either (i) lacking PTEN [36] or by (ii) displaying deficiencies in BAP1 [47]. They underpin the emerging role of altered Ca 2+ signaling at the MAM level as a key event in apoptosis resistance that contributes early events associated with oncogenesis and tumor formation.…”