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Background: The growth factor receptor bound protein 7 (Grb7) family of signalling adaptor proteins comprises Grb7, Grb10 and Grb14. Each can interact with the insulin receptor and other receptor tyrosine kinases, where Grb10 and Grb14 inhibit insulin receptor activity. In cell culture studies they mediate functions including cell survival, proliferation, and migration. Mouse knockout (KO) studies have revealed physiological roles for Grb10 and Grb14 in glucose-regulated energy homeostasis. Both Grb10 KO and Grb14 KO mice exhibit increased insulin signalling in peripheral tissues, with increased glucose and insulin sensitivity and a modestly increased ability to clear a glucose load. In addition, Grb10 strongly inhibits fetal growth such that at birth Grb10 KO mice are 30% larger by weight than wild type littermates. Results: Here, we generate a Grb7 KO mouse model. We show that during fetal development the expression patterns of Grb7 and Grb14 each overlap with that of Grb10. Despite this, Grb7 and Grb14 did not have a major role in influencing fetal growth, either alone or in combination with Grb10. At birth, in most respects both Grb7 KO and Grb14 KO single mutants were indistinguishable from wild type, while Grb7:Grb10 double knockout (DKO) were near identical to Grb10 KO single mutants and Grb10:Grb14 DKO mutants were slightly smaller than Grb10 KO single mutants. In the developing kidney Grb7 had a subtle positive influence on growth. An initial characterisation of Grb7 KO adult mice revealed sexually dimorphic effects on energy homeostasis, with females having a significantly smaller renal white adipose tissue depot and an enhanced ability to clear glucose from the circulation, compared to wild type littermates. Males had elevated fasted glucose levels with a trend towards smaller white adipose depots, without improved glucose clearance. Conclusions: Grb7 and Grb14 do not have significant roles as inhibitors of fetal growth, unlike Grb10, and instead Grb7 may promote growth of the developing kidney. In adulthood, Grb7 contributes subtly to glucose mediated energy homeostasis, raising the possibility of redundancy between all three adaptors in physiological regulation of insulin signalling and glucose handling. [ABSTRACT FROM AUTHOR]

Obesity presents a significant global health challenge, increasing the susceptibility to chronic conditions such as diabetes, cardiovascular disease, and hypertension. Within the context of obesity, lipid metabolism, adipose tissue formation, and inflammation are intricately linked to endoplasmic reticulum stress (ERS). ERS modulates metabolism, insulin signaling, inflammation, as well as cell proliferation and death through the unfolded protein response (UPR) pathway. Serving as a crucial nexus, ERS bridges the functionality of adipose tissue and the inflammatory response. In this review, we comprehensively elucidate the mechanisms by which ERS impacts adipose tissue function and inflammation in obesity, aiming to offer insights into targeting ERS for ameliorating metabolic dysregulation in obesity-associated chronic diseases such as hyperlipidemia, hypertension, fatty liver, and type 2 diabetes. [ABSTRACT FROM AUTHOR]

The regulatory subunit of phosphatidylinositol 3-kinase (PI3K), known as p85, is a critical component in the insulin signaling pathway. Extensive research has shed light on the diverse roles played by the two isoforms of p85, namely p85α and p85b. The gene pik3r1 encodes p85α and its variants, p55α and p50α, while pik3r2 encodes p85β. These isoforms exhibit various activities depending on tissue types, nutrient availability, and cellular stoichiometry. Whole-body or liverspecific deletion of pik3r1 have shown to display increased insulin sensitivity and improved glucose homeostasis; however, skeletal muscle-specific deletion of p85α does not exhibit any significant effects on glucose homeostasis. On the other hand, whole-body deletion of pik3r2 shows improved insulin sensitivity with no significant impact on glucose tolerance. Meanwhile, liver-specific double knockout of pik3r1 and pik3r2 leads to reduced insulin sensitivity and glucose tolerance. In the context of obesity, upregulation of hepatic p85α or p85β has been shown to improve glucose homeostasis. However, hepatic overexpression of p85α in the absence of p50α and p55α results in increased insulin resistance in obese mice. p85α and p85β have distinctive roles in cancer development. p85α acts as a tumor suppressor, but p85β promotes tumor progression. In the immune system, p85α facilitates B cell development, while p85β regulates T cell differentiation and maturation. This review provides a comprehensive overview of the distinct functions attributed to p85α and p85β, highlighting their significance in various physiological processes, including insulin signaling, cancer development, and immune system regulation. [ABSTRACT FROM AUTHOR]

Adiponectin is an antidiabetic endogenous adipokine that plays a protective role against the unfavorable metabolic sequelae of obesity. Recent evidence suggests a sinister link between hypoadiponectinemia and development of insulin resistance/type 2 diabetes (T2D). Adiponectin's insulin‐sensitizing property is mediated through the specific adiponectin receptors R1 and R2, which activate the AMP‐activated protein kinase (AMPK) and peroxisome proliferator‐activated receptor (PPAR) α pathways. AdipoAI is a novel synthetic analogue of endogenous adiponectin with possibly similar pharmacological effects. Thus, there is a need of orally active small molecules that activate Adipoq subunits, and their downstream signaling, which could ameliorate obesity related type 2 diabetes. In the study we aim to investigate the effects of AdipoAI on obesity and T2D. Through in‐vitro and in‐vivo analyses, we investigated the antidiabetic potentials of AdipoAI and compared it with AdipoRON, another orally active adiponectin receptors agonist. Our results showed that in‐vitro treatment of AdipoAI (0–5 µM) increased adiponectin receptor subunits AdipoR1/R2 with increase in AMPK and APPL1 protein expression in C2C12 myotubes. Similarly, in‐vivo, oral administration of AdipoAI (25 mg/kg) observed similar effects as that of AdipoRON (50 mg/kg) with improved control of blood glucose and insulin sensitivity in diet‐induced obesity (DIO) mice models. Further, AdipoAI significantly reduced epididymal fat content with decrease in inflammatory markers and increase in PPAR‐α and AMPK levels and exhibited hepatoprotective effects in liver. Further, AdipoAI and AdipoRON also observed similar results in adipose tissue. Thus, our results suggest that low doses of orally active small molecule agonist of adiponectin AdipoAI can be a promising therapeutic target for obesity and T2D. Significance statement: Obesity is a global health concern, having doubled in more than 70 countries and resulting in an escalation of obesity‐related diseases, such as type 2 diabetes (T2D). The adiponectin receptors (AdipoR1 and AdipoR2) have emerged as important targets for controlling inflammation, obesity and T2D. To maximize the potential of adiponectin receptors in targeting the fundamental etiopathology of obesity and T2D, we have designed, synthesized, Adiponectin receptor agonist named AdipoAI (standing for anti‐inflammation) which in our preclinical trials on high fat diet (HFD) observed reduced glucose resistance, insulin tolerance, promoted adiponectin signaling in liver and adipose tissues of obese mice, and resulted decrease liver inflammation. Thus, our trial has affirmed AdipoAI as a potent adiponectin agonist with antidiabetic, hepatoprotective, and anti‐inflammatory properties. [ABSTRACT FROM AUTHOR]

Adipokines are proteins secreted by adipose tissue to regulate glucolipid metabolism and play vital roles in our body. Different adipokines have more than one endocrine function and be divided into several different categories according to their functions, including adipokines involved in glucolipid metabolism, the inflammatory response, insulin action, activation of brown adipose tissue (BAT) and appetite regulation. Multiple adipokines interact with each other to regulate metabolic processes. Based on the recent progress of adipokine research, this article discusses the role and mechanism of various adipokines in glucolipid metabolism, which may provide new ideas for understanding the pathogenesis and improving the treatment of various metabolic diseases. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the association between diverse surrogate markers of insulin resistance and adiponectin concentrations. Methods: Four hundred healthy participants were included. Two different cohorts were formed according to the body mass index (BMI) values. Group 1 (n = 200) consisted of individuals with normal BMI values (18.50–24.99 kg/m2), whereas in Group 2 (n = 200) there were overweight or obese individuals (BMI ≥25.00 kg/m2). Homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and triglycerides–glucose index (TyG) were calculated. Serum adiponectin levels were measured by ELISA. A correlation analysis was performed to assess the association between serum adiponectin and HOMA-IR, QUICKI, and TyG. Results: Participants in Group 2 were older (age in years: Group 1, 33.3 ± 6.8 vs. Group 2, 36.4 ± 7.0, P < 0.001). There was no gender difference between groups. Overweight or obese participants had higher BMI, waist circumference, fat mass, fat ratio, fasting plasma glucose, fasting plasma insulin, triglycerides, total cholesterol, and low-density lipoprotein cholesterol values, whereas high-density lipoprotein cholesterol was higher in participants with normal BMI measures. Overweight or obese subjects were more insulin resistant (higher TyG index and HOMA-IR) and less insulin sensitive (lower QUICKI), P < 0.001 for all. Serum adiponectin levels were lower in Group 2 (serum adiponectin in ng/mL: Group 1, 11,880 ± 6838 vs. Group 2, 9115 ± 5766, P < 0.001). The correlation between TyG index and adiponectin was stronger than the correlation between QUICKI and adiponectin, and HOMA-IR and adiponectin (r for TyG and adiponectin −0.408, r for QUICKI and adiponectin 0.394, r for HOMA-IR and adiponectin −0.268, respectively, P < 0.001 for all correlations). Conclusions: TyG has a stronger association with adiponectin than HOMA-IR and QUICKI. [ABSTRACT FROM AUTHOR]

Aging slowly erodes skeletal muscle strength and mass, eventually leading to profound functional deficits and muscle atrophy. The molecular mechanisms of skeletal muscle aging are not well understood. To better understand mechanisms of muscle aging, we investigated the potential role of ATF4, a transcription regulatory protein that can rapidly promote skeletal muscle atrophy in young animals deprived of adequate nutrition or activity. To test the hypothesis that ATF4 may be involved in skeletal muscle aging, we studied fed and active muscle-specific ATF4 knockout mice (ATF4 mKO mice) at 6 months of age, when wild-type mice have achieved peak muscle mass and function, and at 22 months of age, when wild-type mice have begun to manifest age-related muscle atrophy and weakness. We found that 6-month-old ATF4 mKO mice develop normally and are phenotypically indistinguishable from 6-month-old littermate control mice. However, as ATF4 mKO mice become older, they exhibit significant protection from age-related declines in strength, muscle quality, exercise capacity, and muscle mass. Furthermore, ATF4 mKO muscles are protected from some of the transcriptional changes characteristic of normal muscle aging (repression of certain anabolic mRNAs and induction of certain senescence-associated mRNAs), and ATF4 mKO muscles exhibit altered turnover of several proteins with important roles in skeletal muscle structure and metabolism. Collectively, these data suggest ATF4 as an essential mediator of skeletal muscle aging and provide new insight into a degenerative process that impairs the health and quality of life of many older adults. [ABSTRACT FROM AUTHOR]

Background: Skeletal muscle is the largest tissue in the body, and it affects motion, metabolism and homeostasis. Skeletal muscle development comprises myoblast proliferation, fusion and differentiation to form myotubes, which subsequently form mature muscle fibres. This process is strictly regulated by a series of molecular networks. Increasing evidence has shown that noncoding RNAs, especially microRNAs (miRNAs), play vital roles in regulating skeletal muscle growth. Here, we showed that miR-668-3p is highly expressed in skeletal muscle. Methods: Proliferating and differentiated C2C12 cells were transfected with miR-668-3p mimics and/or inhibitor, and the mRNA and protein levels of its target gene were evaluated by RT‒qPCR and Western blotting analysis. The targeting of Appl1 by miR-668-3p was confirmed by dual luciferase assay. The interdependence of miR-668-3p and Appl1 was verified by cotransfection of C2C12 cells. Results: Our data reveal that miR-668-3p can inhibit myoblast proliferation and myogenic differentiation. Phosphotyrosine interacting with PH domain and leucine zipper 1 (Appl1) is a target gene of miR-668-3p, and it can promote myoblast proliferation and differentiation by activating the p38 MAPK pathway. Furthermore, the inhibitory effect of miR-668-3p on myoblast cell proliferation and myogenic differentiation could be rescued by Appl1. Conclusion: Our results indicate a new mechanism by which the miR-668-3p/Appl1/p38 MAPK pathway regulates skeletal muscle development. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) represents one of the fastest growing epidemic metabolic disorders worldwide and is a strong contributor for a broad range of comorbidities, including vascular, visual, neurological, kidney, and liver diseases. Moreover, recent data suggest a mutual interplay between T2DM and Corona Virus Disease 2019 (COVID-19). T2DM is characterized by insulin resistance (IR) and pancreatic ß cell dysfunction. Pioneering discoveries throughout the past few decades have established notable links between signaling pathways and T2DM pathogenesis and therapy. Importantly, a number of signaling pathways substantially control the advancement of core pathological changes in T2DM, including IR and ß cell dysfunction, as well as additional pathogenic disturbances. Accordingly, an improved understanding of these signaling pathways sheds light on tractable targets and strategies for developing and repurposing critical therapies to treat T2DM and its complications. In this review, we provide a brief overview of the history of T2DM and signaling pathways, and offer a systematic update on the role andmechanism of key signaling pathways underlying the onset, development, and progression of T2DM. In this content, we also summarize current therapeutic drugs/agents associated with signaling pathways for the treatment of T2DM and its complications, and discuss some implications and directions to the future of this field. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by hyperandrogenism and follicular arrest. Electroacupuncture (EA) has been shown to be effective at improving hyperandrogenism and follicular arrest in PCOS; however, its mechanism of action remains to be deciphered. Objective: In this study, we investigated whether EA improved follicular development in an obese rat model of PCOS and regulated the expression of adiponectin, AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC). Methods: EA was administered at CV3, CV4 and ST40. Changes in body weight, paraovarian fat, estrus cycle, ovarian morphology, levels of related hormones, and glucose and lipid metabolism were evaluated. In addition, protein and mRNA expression of adiponectin, AMPK and ACC was measured. Results: The body weight and paraovarian fat of rats in the EA group were reduced, while estrus cyclicity and ovarian morphology improved. Levels of free fatty acids, triglycerides, total cholesterol and low-density lipoprotein cholesterol were significantly reduced in the EA group, as well as blood glucose levels. Furthermore, levels of testosterone and luteinizing hormone were reduced in the EA group, while estradiol levels were increased. Protein and mRNA expression of adiponectin, AMPKα1 and liver kinase B1 (LKB1) was found to be increased in the EA group, while protein and mRNA expression of ACC were significantly reduced. Conclusion: Our findings suggest that EA improved follicular development and metabolism and regulated expression levels of adiponectin, AMPKα1, LKB1 and ACC in our obese rat model of PCOS. [ABSTRACT FROM AUTHOR]

Objectives: Skeletal muscle mass and function deteriorate with ageing. Adiponectin receptors (APNrs), mainly activated by adiponectin, participate in various physiological activities and have varying signalling pathways at different ages. This study aimed to explore whether discrepant performance exists in APNr activation regulating young and aged muscle satellite cells (MUSCs) and whether age‐related muscle dysfunction could be alleviated upon APNr activation. Methods: The gastrocnemius muscle phenotype was observed in male mice aged 2 and 18 months. An APNr agonist (AdipoRon) was used in vitro and in vivo to investigate the changes in cell biological behaviours and whether muscle dysfunction could be retarded after APNr activation. Results: Aged mice exhibited decreased muscle mass and increased fat infiltration. APNr activation inhibited C2C12 cells and young MUSCs (YMUSCs) proliferation but showed no obvious effect on aged MUSCs (AMUSCs). Moreover, APNr activation inhibited the migration of both YMUSCs and AMUSCs. Interestingly, APNr activation hampered the myogenic differentiation but advanced the adipogenic differentiation of YMUSCs, yet exact opposite results were presented in AMUSCs. It was demonstrated that Wnt and PI3K signalling pathways may mediate the phenotypic differences. Furthermore, in vivo experiments verified that APNr activation ameliorated age‐related muscle atrophy and excessive fat infiltration. Conclusions: APNr activation exerted dual effects on the regulation of myogenesis and adipogenesis of YMUSCs and AMUSCs and rescued age‐related skeletal muscle dysfunction. [ABSTRACT FROM AUTHOR]

In clinical trials, biochemical markers provide useful information on the drug's mode of action, therapeutic response and side effect monitoring and can act as surrogate endpoints. In pharmacological intervention development for sarcopenia management, there is an urgent need to identify biomarkers to measure in clinical trials and that could be used in the future in clinical practice. The objective of the current consensus paper is to provide a clear list of biochemical markers of musculoskeletal health and aging that can be recommended to be measured in Phase II and Phase III clinical trials evaluating new chemical entities for sarcopenia treatment. A working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) proposed classifying biochemical markers into 2 series: biochemical markers evaluating musculoskeletal status and biochemical markers evaluating causal factors. For series 1, the group agreed on 4 biochemical markers that should be assessed in Phase II or Phase III trials (i.e., Myostatin-Follistatin, Brain Derived Neurotrophic Factor, N-terminal Type III Procollagen and Serum Creatinine to Serum Cystatin C Ratio – or the Sarcopenia Index). For series 2, the group agreed on 6 biochemical markers that should be assessed in Phase II trials (i.e., the hormones insulin-like growth factor-1 (IGF-I), dehydroepiandrosterone sulphate, and cortisol, and the inflammatory markers C-reactive protein (CRP), interleukin-6 and tumor necrosis factor-α), and 2 in Phase III trials (i.e., IGF-I and CRP). The group also proposed optional biochemical markers that may provide insights into the mode of action of pharmacological therapies. Further research and development of new methods for biochemical marker assays may lead to the evolution of these recommendations. [ABSTRACT FROM AUTHOR]

The AKT‐mTOR pathway is a central regulator of cell growth and metabolism. Upon sustained mTOR activity, AKT activity is attenuated by a feedback loop that restrains upstream signaling. However, how cells control the signals that limit AKT activity is not fully understood. Here, we show that MASTL/Greatwall, a cell cycle kinase that supports mitosis by phosphorylating the PP2A/B55 inhibitors ENSA/ARPP19, inhibits PI3K‐AKT activity by sustaining mTORC1‐ and S6K1‐dependent phosphorylation of IRS1 and GRB10. Genetic depletion of MASTL results in an inefficient feedback loop and AKT hyperactivity. These defects are rescued by the expression of phosphomimetic ENSA/ARPP19 or inhibition of PP2A/B55 phosphatases. MASTL is directly phosphorylated by mTORC1, thereby limiting the PP2A/B55‐dependent dephosphorylation of IRS1 and GRB10 downstream of mTORC1. Downregulation of MASTL results in increased glucose uptake in vitro and increased glucose tolerance in adult mice, suggesting the relevance of the MASTL‐PP2A/B55 kinase‐phosphatase module in controlling AKT and maintaining metabolic homeostasis. Synopsis: In the presence of excessive signaling, the AKT‐mTOR pathway limits its activity by phosphorylating upstream regulators. When phosphorylated by mTOR, the MASTL/Greatwall kinase contributes to this negative feedback loop by inhibiting the phosphatase PP2A to prevent excessive AKT activity. MASTL is a new component of the feedback loop that restricts mTOR activity.MASTL inhibits dephosphorylation of IRS1 and GRB10 by PP2A/B55.mTOR phosphorylates and activates MASTL to inhibit PP2A/B55.MASTL inhibition results in improved glucose homeostasis in vivo. [ABSTRACT FROM AUTHOR]

Background: Lung cancer (LC) is the most frequent caner type and causes the most cancer-related death. Brain metastases (BM) are the deadliest complications of lung cancer, and the prognostic biomarkers of BM are urgently needed. Materials and methods: In our study, we established an inception cohort including 122 patients with asynchronous BM from NSCLC, and further selected 70 patients who received surgical resection, which compromised the validation cohort. With immunohistochemistry, we investigated the expression of WDR5 in the cohort. By chi-square method, the correlations between WDR5 and clinicopathological factors were analyzed. The prognostic indicators were analyzed with the univariate analysis, and independent prognostic factors were identified by multivariate analysis with Coxregression model. Results: WDR5 is frequently expressed in the cytoplasm of BM from NSCLC. Patients with low or high expression of WDR5 account for 60% and 40% respectively. High expression of WDR5 indicates poor prognosis of BM from NSCLC (P=0.001). In addition to WDR5, KPS is also a prognostic factor of BM, and high KPS predicts favorable prognosis (P=0.006). WDR5 is an independent prognostic biomarker for poor prognosis of BM from NSCLC, with the cancerrelated odds as 2.48. Conclusions: High expression of WDR5 can predict the poor prognosis of BM, and WDR5 is an independent prognostic biomarker of BM from NSCLC. Patients with WDR5 overexpression are more high-risk to suffer BM-related death and should receive more intense post-operational supervision. [ABSTRACT FROM AUTHOR]

An imbalance of human mesenchymal stem cells (hMSCs) adipogenic and osteogenic differentiation is crucial in the pathogenesis of osteoporosis, and elucidation of the underlying mechanism is urgently needed. APPL1, an adaptor protein of the adiponectin receptor, was recently shown to be closely related to bone mass. However, the role of APPL1 in the imbalance of hMSC differentiation in osteoporosis is unclear. Therefore, we aimed to explore the mechanisms by which APPL1 alters hMSCs adipogenic differentiation in osteoporosis. Here, we found that APPL1 expression was downregulated in elderly patients with osteoporosis and in mouse osteoporosis model. APPL1 negatively regulated hMSC adipogenic differentiation in vivo and in vitro. Mechanistically, by enhancing ubiquitination-mediated Myoferlin degradation, downregulated APPL1 expression increased the risk of lysosome dysfunction during hMSCs adipogenic differentiation. Lysosomal dysfunction inhibited autophagy flux by suppressing autophagosome degradation and promoted hMSC differentiation towards the adipocyte lineage. Our findings suggest that APPL1/Myoferlin downregulation promoted hMSCs adipogenic differentiation by inhibiting autophagy flux, further impairing the balance of hMSCs adipogenic and osteogenic differentiation in osteoporosis; the APPL1/ Myoferlin axis may be a promising diagnostic and therapeutic target for osteoporosis. [ABSTRACT FROM AUTHOR]

Background: The pathophysiology of diabetic retinopathy (DR) is multifaced. A low level of circulating adiponectin (APN) in type 2 diabetes is associated with microvasculature complications, and its role in the evolution of DR is complex. Aim: This study is designed to explore the potential impact of APN in the pathogenesis of DR, linking the changes in cellular and biological processes with the pathways, networks, and regulators involved in its actions. Methods: Human microvascular retinal endothelial cells (HMRECs) were exposed to 30mM glucose (HG) and treated with globular adiponectin (30μg/mL) for 24 hours. The cells were evaluated for reactive oxidative stress (ROS) and apoptosis. RT-PCR profile arrays were utilized to evaluate the profile of genes involved in endothelial functions, angiogenesis, extracellular matrix, and adhesion molecules for hyperglycemic HMRECs treated with adiponectin. In addition, the barrier function, leukocyte migration, and angiogenesis were evaluated. The differential expressed genes (DEGs) were outlined, and bioinformatic analysis was applied. Results: Adiponectin suppresses ROS production and apoptosis in HMRECs under HG conditions. Adiponectin improved migration and barrier functions in hyperglycemic cells. The bioinformatic analysis highlighted that the signaling pathways of integrin, HMGB1, and p38 AMPK, are mainly involved in the actions of APN on HMRECs. APN significantly affects molecular functions, including the adhesion of cells, chemotaxis, migration of WBCs, and angiogenesis. STAT3, NFKB, IKBKB, and mir-8 are the top upstream regulators, which affect the expressions of the genes of the data set, while TNF and TGFB1 are the top regulators. Conclusion: Adiponectin significantly counteracts hyperglycemia at various cellular and molecular levels, reducing its impact on the pathophysiological progression towards DR in vitro using HMRECs. Adiponectin ameliorates inflammatory response, oxidative stress, and endothelial barrier dysfunction using a causal network of NFBk complex, TNF, and HMGB1 and integrin pathways. [ABSTRACT FROM AUTHOR]

3-phosphoinositide-dependent kinase 1 (PDK1) is an essential serine/threonine protein kinase, which plays a crucial role in cell growth and proliferation. It is often referred to as a 'master' kinase due to its ability to activate at least 23 downstream protein kinases implicated in various signaling pathways. In this study, we have elucidated the mechanism of phosphoinositide-driven PDK1 auto-activation. We show that PDK1 trans-autophosphorylation is mediated by a PIP3-mediated face-to-face dimer. We report regulatory motifs in the kinase-PH interdomain linker that allosterically activate PDK1 autophosphorylation via a linker-swapped dimer mechanism. Finally, we show that PDK1 is autoinhibited by its PH domain and that positive cooperativity of PIP3 binding drives switch-like activation of PDK1. These results imply that the PDK1-mediated activation of effector kinases, including Akt, PKC, Sgk, S6K and RSK, many of whom are not directly regulated by phosphoinositides, is also likely to be dependent on PIP3 or PI(3,4)P2. The essential protein kinase PDK1 is activated by phospoinositide-mediated dimerization and trans-autophosphorylation. Here, the authors show that in the absence of PIP3 or PI(3,4)P2 phosphoinositides, PDK1 is maintained in an inactive, autoinhibited conformation in the cytosol. [ABSTRACT FROM AUTHOR]

Background: Diagnosis of mature-onset diabetes of the young (MODY), a non-autoimmune monogenic form of diabetes mellitus, is confirmed by genetic testing. However, a positive genetic diagnosis is achieved in only around 50% of patients with clinical characteristics of this disease.Results: We evaluated the diagnostic utility of transcriptomic analysis in patients with clinical suspicion of MODY but a negative genetic diagnosis. Using Nanostring nCounter technology, we conducted transcriptomic analysis of 19 MODY-associated genes in peripheral blood samples from 19 patients and 8 healthy controls. Normalized gene expression was compared between patients and controls and correlated with each patient's biochemical and clinical variables. Z-scores were calculated to identify significant changes in gene expression in patients versus controls. Only 7 of the genes analyzed were detected in peripheral blood. HADH expression was significantly lower in patients versus controls. Among patients with suspected MODY, GLIS3 expression was higher in obese versus normal-weight patients, and in patients aged < 25 versus > 25 years at diabetes onset. Significant alteration with respect to controls of any gene was observed in 57.9% of patients.Conclusions: Although blood does not seem to be a suitable sample for transcriptomic analysis of patients with suspected MODY, in our study, we detected expression alterations in some of the genes studied in almost 58% of patients. That opens the door for future studies that can clarify the molecular cause of the clinic of these patients and thus be able to maintain a more specific follow-up and treatment in each case. [ABSTRACT FROM AUTHOR]

One of the most important side effects of chemotherapy is cardiovascular complications, such as cardiotoxicity. Many factors are involved in the pathogenesis of cardiotoxicity; one of the most important of which is long non-coding RNAs (lncRNAs). lncRNA has 200–1000 nucleotides. It is involved in important processes such as cell proliferation, regeneration and apoptosis; today it is used as a prognostic and diagnostic factor. A, various drugs by acting on lncRNAs can affect cells. Therefore, by accurately identifying IncRNAs function, we can play an effective role in preventing the development of cardiotoxicity-induced chemotherapy drugs, and use them as a therapeutic strategy to improve clinical symptoms and increase patient survival. [ABSTRACT FROM AUTHOR]

Skeletal muscle stem cells, also called Satellite Cells (SCs), are actively maintained in quiescence but can activate quickly upon extrinsic stimuli. However, the mechanisms of how quiescent SCs (QSCs) activate swiftly remain elusive. Here, using a whole mouse perfusion fixation approach to obtain bona fide QSCs, we identify massive proteomic changes during the quiescence-to-activation transition in pathways such as chromatin maintenance, metabolism, transcription, and translation. Discordant correlation of transcriptomic and proteomic changes reveals potential translational regulation upon SC activation. Importantly, we show Cytoplasmic Polyadenylation Element Binding protein 1 (CPEB1), post-transcriptionally affects protein translation during SC activation by binding to the 3′ UTRs of different transcripts. We demonstrate phosphorylation-dependent CPEB1 promoted Myod1 protein synthesis by binding to the cytoplasmic polyadenylation elements (CPEs) within its 3′ UTRs to regulate SC activation and muscle regeneration. Our study characterizes CPEB1 as a key regulator to reprogram the translational landscape directing SC activation and subsequent proliferation. Skeletal muscle stem cells are actively maintained in quiescence, but can activate quickly upon extrinsic stimulation. Here the authors show that CPEB1 promotes muscle stem cell activation by reprogramming the translational landscape. [ABSTRACT FROM AUTHOR]

Alopecia induced by aging or side effects of medications affects millions of people worldwide and impairs the quality of life; however, there is a limit to the current medications. Here, we identify a small transdermally deliverable 5-mer peptide (GLYYF; P5) that activates adiponectin receptor 1 (AdipoR1) and promotes hair growth. P5 sufficiently reproduces the biological effect of adiponectin protein via AMPK signaling pathway, increasing the expression of hair growth factors in the dermal papilla cells of human hair follicle. P5 accelerates hair growth ex vivo and induces anagen hair cycle in mice in vivo. Furthermore, we elucidate a key spot for the binding between AdipoR1 and adiponectin protein using docking simulation and mutagenesis studies. This study suggests that P5 could be used as a topical peptide drug for alleviating pathological conditions, which can be improved by adiponectin protein, such as alopecia. [ABSTRACT FROM AUTHOR]

Lipid metabolism is closely related to the improvement of vascular calcification (VC) in chronic kidney disease (CKD). Globular adiponectin (gAd) has been reported to be involved in the development of VC in CKD, but the detailed regulatory role remains unclear. The present study is aimed to investigate the biological function and the underlying regulation mechanism of gAd in the process of VC during CKD. Vascular smooth muscle cells (VSMCs) calcification was determined by Alizarin Red S staining. Protein signaling related with VC was tested by western blotting. The expression and intracellular localization of runt-related transcription factor 2 (Runx2) was detected by immunofluorescence and uraemic rat with VC was established by a two-step nephrectomy. Combined with the results of Alizarin Red S staining, we discovered that β-glycerophosphate (β-Gp)-induced the osteoblastic differentiation of VSMCs was significantly reversed by gAd treatment. Along with the VSMCs calcification and the increase of Runx2 in β-Gp-exposed VSMCs, the activities of protein kinase B (AKT) and Wnt/β-catenin pathway were enhanced, but that were counteracted by the exposure of gAd in rat and human VSMCs. After administration with agonists of the Wnt (SKL2001) and AKT (SC79), there appeared more osteoblastic differentiation and higher expression of Runx2 in gAd-treated VSMCs, but showing lower impact in the presence of SC79 than that in the presence of SKL2001. In the in vivo experiments, intravenous injection of gAd also significantly inhibited VC and Runx2 level in uraemic rat in a dose-dependent manner, possibly through regulating Wnt/β-catenin pathway. This study demonstrates that gAd ameliorates osteoblastic differentiation of VSMCs possibly by blocking PI3K/AKT and Wnt/β-catenin signaling transduction. The findings provide an important foundation for gAd in treating VC in kidney diseases. [ABSTRACT FROM AUTHOR]

Glucose and lipid metabolisms are central in determining the growth and the health status of cultured fish and thus are of pivotal interest for modern aquaculture. Adiponectin is a fat‐derived hormone that plays a vital role in glucose and lipid homeostasis. While abundant knowledge is available on adiponectin in mammals, less is known in fish, though it has been documented that adiponectin is certainly important in the modulation of teleosts' lipid and glucose metabolism too. Adiponectin exerts its metabolic effects via two receptors, AdipoR1 and AdipoR2, which then, in a tissue‐dependent manner, initiate a series of signal transduction events, eventually resulting in increased glucose utilization and fatty acid β‐oxidation. In teleosts, adiponectin and its receptors genes were first identified in zebrafish in 2008, and since then, increasing numbers of adiponectin and its receptors have been cloned in a variety of cultured fish species. This review attempts to provide the first, thorough overview of the discovery and identification of adiponectin, its receptors and their expression, regulation and signal transduction in fish. Then, the potential effects and mechanisms of adiponectin on energy (lipid and glucose) homeostasis are described, before concluding on possible therapeutic approaches to enhance adiponectin actions. It is envisaged that the present work will contribute, first, to knowledge gain in the evolution of energy homeostasis in vertebrates, and then, to provide a much‐needed additional theoretical fundament for a healthier and further performance‐improved aquaculture. [ABSTRACT FROM AUTHOR]

Adiponectin is an adipokine that exerts insulin-sensitizing and anti-inflammatory roles in insulin target tissues including liver. While the insulin-sensitizing function of adiponectin has been extensively investigated, the precise mechanism by which adiponectin alleviates diet-induced hepatic inflammation remains elusive. Here, we report that hepatocyte-specific knockout (KO) of the adaptor protein APPL2 enhanced adiponectin sensitivity and prevented mice from developing high-fat diet-induced inflammation, insulin resistance, and glucose intolerance, although it caused fatty liver. The improved anti-inflammatory and insulin-sensitizing effects in the APPL2 hepatocyte-specific KO mice were largely reversed by knocking out adiponectin. Mechanistically, hepatocyte APPL2 deficiency enhances adiponectin signaling in the liver, which blocks TNF-α-stimulated MCP-1 expression via inhibiting the mTORC1 signaling pathway, leading to reduced macrophage infiltration and thus reduced inflammation in the liver. With results taken together, our study uncovers a mechanism underlying the anti-inflammatory role of adiponectin in the liver and reveals the hepatic APPL2-mTORC1-MCP-1 axis as a potential target for treating overnutrition-induced inflammation in the liver. [ABSTRACT FROM AUTHOR]

Background: The signal transducer and activator of transcription 6 (STAT6) transcription factor plays a vitally important role in immune cells, where it is activated mainly by interleukin-4 (IL-4). Because IL-4 is an essential cytokine for myotube formation, STAT6 might also be involved in myogenesis as part of IL-4 signaling. This study was conducted to elucidate the role of STAT6 in adult myogenesis in vitro and in vivo. Methods: Myoblasts were isolated from male mice and were differentiated on a culture dish to evaluate the change in STAT6 during myotube formation. Then, the effects of STAT6 overexpression and inhibition on proliferation, differentiation, and fusion in those cells were studied. Additionally, to elucidate the myogenic role of STAT6 in vivo, muscle regeneration after injury was evaluated in STAT6 knockout mice. Results: IL-4 can increase STAT6 phosphorylation, but STAT6 phosphorylation decreased during myotube formation in culture. STAT6 overexpression decreased, but STAT6 knockdown increased the differentiation index and the fusion index. Results indicate that STAT6 inhibited myogenin protein expression. Results of in vivo experiments show that STAT6 knockout mice exhibited better regeneration than wild-type mice 5 days after cardiotoxin-induced injury. It is particularly interesting that results obtained using cells from STAT6 knockout mice suggest that this STAT6 inhibitory action for myogenesis was not mediated by IL-4 but might instead be associated with p38 mitogen-activated protein kinase phosphorylation. However, STAT6 was not involved in the proliferation of myogenic cells in vitro and in vivo. Conclusion: Results suggest that STAT6 functions as an inhibitor of adult myogenesis. Moreover, results suggest that the IL-4-STAT6 signaling axis is unlikely to be responsible for myotube formation. [ABSTRACT FROM AUTHOR]

Nowadays, the complications related to diabetes, such as nephropathy, cardiovascular problems, and aging, are highly being considered. Renal cell aging is affected by various mechanisms of inflammation, oxidative stress, and basement membrane thickening, which are significant causes of renal dysfunction in diabetes. Due to recent studies, adiponectin plays a key role in diabetes-related kidney diseases as a fat-derived hormone. In diabetes, reduced adiponectin levels are associated to renal cell aging. Oxidative stress and related signaling pathways are the main routes in which adiponectin may be effective to decline diabetes-associated aging. Therefore, adiponectin signaling in target tissues becomes one of the research areas of interest in metabolism and clinical medicine. Studies on adiponectin signaling will increase our understanding of adiponectin role in diabetes-linked diseases as well as shortening life span conditions which may guide the design of antidiabetic and anti-aging drugs. [ABSTRACT FROM AUTHOR]

Adiponectin, an adipokine that circulates as multiple multimeric complexes at high levels in serum, has antidiabetic, anti-inflammatory, antiatherogenic, and cardioprotective properties. Understanding the mechanisms regulating adiponectin's physiological effects is likely to provide critical insight into the development of adiponectin-based therapeutics to treat various metabolic-related diseases. In this review, we summarize our current understanding on adiponectin action in its various target tissues and in cellular models. We also focus on recent advances in two particular regulatory aspects; namely, the regulation of adiponectin gene expression, multimerization, and secretion, as well as extravasation of circulating adiponectin to the interstitial space and its degradation. Finally, we discuss some potential therapeutic approaches using adiponectin as a target and the current challenges facing adiponectin-based therapeutic interventions. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic inflammatory disorder marked by synovitis, ultimately leading to cartilage and bone destruction. In RA, adiponectin levels are increased in serum and synovial fluid. Adiponectin belongs to the adipokines, a group of highly bioactive substances secreted by adipocytes and other cell types. It has been shown to induce the production of proinflammatory and prodestructive factors by human RA synovial fibroblasts (RASF), suggesting a role in the pathophysiology of the disease. Although adenosine monophosphate-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK) are known to be involved in adiponectin signaling in RASF, no literature is available about whether the different adiponectin isoforms affect AMPK and p38 MAPK signaling in the same manner. In this study, we elucidated the signaling mechanisms in RASF, activated in response to selective stimulation with the 2 biologically most potent adiponectin isoforms, and possible approaches to inhibit adiponectin-mediated effects in RASF. All adiponectin isoforms induced p38 MAPK and AMPK phosphorylation to various degrees. Blocking AMPK activation increased p38 MAPK phosphorylation, while blocking p38 MAPK activation increased AMPK phosphorylation, both independent of the effect of adiponectin. Neither AMPKα1 nor AMPKα2 knockdown reduced interleukin (IL)-6/IL-8 release. Targeting transforming growth factor-activated kinase 1 (TAK1), a signaling molecule upstream of p38 MAPK, reduced the IL-6/IL-8 release. Taken together, our study showed that, in the case of adiponectin isoforms, inhibiting the p38 MAPK or the AMPK signaling pathway individually is not sufficient, probably due to compensatory interactions between these pathways. TAK1 might provide an alternative approach by ameliorating the proinflammatory effects of adiponectin in RA. Our results do not suggest that targeting individual adiponectin isoforms specifically in RA would provide a benefit over targeting adiponectin as a whole. However, whether targeting individual adiponectin isoforms would allow minimizing the loss of the beneficial effects of adiponectin within the metabolic and cardiovascular system still needs further investigation. [ABSTRACT FROM AUTHOR]

The ADIPOR1 and ADIPOR2 proteins (ADIPORs) are generally considered as adiponectin receptors with anti-diabetic properties. However, studies on the yeast and C. elegans homologs of the mammalian ADIPORs, and of the ADIPORs themselves in various mammalian cell models, support an updated/different view. Based on findings in these experimental models, the ADIPORs are now emerging as evolutionarily conserved regulators of membrane homeostasis that do not require adiponectin to act as membrane fluidity sensors and regulate phospholipid composition. More specifically, membrane rigidification activates ADIPOR signaling to promote fatty acid desaturation and incorporation of polyunsaturated fatty acids into membrane phospholipids until fluidity is restored. The present review summarizes the evidence supporting this new view of the ADIPORs, and briefly examines physiological consequences. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia is a progressive loss of skeletal muscle mass whose pathophysiology has been proposed to possibly involve mechanisms of altered inflammatory status and endocrine function. Adiponectin has been shown to modulate inflammatory status and muscle metabolism. However, the possible association between adiponectin levels and sarcopenia is poorly understood. In order to fill this gap, in the present manuscript we aimed to summarize the current evidence with a systematic review and a meta-analysis of studies reporting serum adiponectin levels in patients with sarcopenia compared to non-sarcopenic controls. Methods: An electronic search through Medline/PubMed, Cochrane Library, and Science Direct was performed till March 1, 2020. From the included papers, meta-analysis of cross-sectional studies comparing serum levels of adiponectin between patients with sarcopenia and controls was performed. Results: Out of 1,370 initial studies, seven studies were meta-analyzed. Sarcopenic participants had significantly higher levels of adiponectin Hedges' g with 95% confidence interval (CI): 1.20 (0.19–2.22), p = 0.02 than controls. Subgroup analysis, performed in Asian population and focused on identification of the condition based on AWGS criteria, reported higher adiponectin levels in sarcopenic population (2.1 (0.17–4.03), p = 0.03 and I2 = 98.98%. Meta-regression analysis revealed female gender to significantly influence the results as demonstrated by beta = 0.14 (95% CI (0.010–0.280), p = 0.040). Conclusions: Our meta-analysis found evidence that sarcopenia is associated with higher adiponectin levels. However, caution is warranted on the interpretation of these findings, and future longitudinal research is required to disentangle and better understand the topic. [ABSTRACT FROM AUTHOR]

The protein kinase with PAS domains (PASK) is a nutrient and energy sensor located in the cells of multiple organs. Many of the recent findings for understanding PASK functions in mammals have been reported in studies involving PASK-deficient mice. This minireview summarizes the PASK role in the control of fasting and feeding responses, focusing especially on the hypothalamus and liver. In 2013, PASK was identified in the hypothalamic areas involved in feeding behavior, and its expression was regulated under fasting/refeeding conditions. Furthermore, it plays a role in coordinating the activation/inactivation of the hypothalamic energy sensors AMPK and mTOR/S6K1 pathways in response to fasting. On the other hand, PASK deficiency prevents the development of obesity and non-alcoholic fatty liver in mice fed with a high-fat diet. This protection is explained by the re-establishment of several high-fat diet metabolic alterations produced in the expression of hepatic transcription factors and key enzymes that control the main metabolic pathways involved in maintaining metabolic homeostasis in fasting/feeding responses. This minireview covers the effects of PASK inactivation in the expression of certain transcription factors and target enzymes in several metabolic pathways under situations such as fasting and feeding with either a standard or a high-fat diet. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Adiponectin stimulates mitochondrial biogenesis through peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), a major regulator of mitochondrial biogenesis. MOTS-c (mitochondrial open reading frame of the 12S rRNA) is a biologically active mitochondrial-derived peptide encoded by mitochondrial DNA. It influences the mechanisms of obesity and diabetes. We hypothesised that the adiponectin pathway may regulate the production and/or secretion of MOTS-c in skeletal muscle. We aimed to determine whether exercise and adiponectin affect MOTS-c to improve insulin resistance in mice. Methods: To investigate this hypothesis, we used wild-type C57BL/6 mice subjected to high-fat diet, an exercise regimen, and i.p. injection of recombinant mouse adiponectin (Acrp30) or MOTS-c, and adiponectin knockout (Adipoq−/−) mice (C57BL/6 background) subjected to i.p. injection of Acrp30. C2C12 myotubes were also treated with sirtuin 1 (SIRT1) inhibitor, PGC-1α inhibitor, SIRT1 activator, plasmid-expressed active APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper), pcDNA-SIRT1, or siRNA against APPL1, SIRT1 or PGC-1α. Results: In Adipoq–/– mice, MOTS-c levels in the plasma and skeletal muscle were downregulated. In C2C12 myotubes, adiponectin increased the mRNA expression of MOTS-c. APPL1 protein level following adiponectin treatment positively correlated with MOTS-c protein and mRNA levels in C2C12 myotubes. SIRT1 overexpression increased the adiponectin-induced mRNA and protein expression of MOTS-c, SIRT1 and PGC-1α. Pharmacologic and genetic inhibition of PGC-1α suppressed the increases in MOTS-c mRNA and protein levels induced by SIRT1 overexpression. In mice, plasma and skeletal muscle MOTS-c levels were significantly downregulated following high-fat-diet. Exercise and i.p. Acrp30 or MOTS-c increased MOTS-c levels and adiponectin mRNA and protein expression in the plasma and skeletal muscle. Conclusions/interpretation: Our findings showed that the APPL1–SIRT1–PGC-1α pathway regulates the production and/or secretion of skeletal muscle MOTS-c by mediating adiponectin signalling. Our study provides an insight into the cellular and molecular pathways underlying the pathogenesis of diabetes and shows that MOTS-c is a potential novel therapeutic target in the treatment of diabetes. [ABSTRACT FROM AUTHOR]

The steroid hormone progesterone (P4) mediates many physiological processes through either nuclear receptors that modulate gene expression or membrane P4 receptors (mPRs) that mediate nongenomic signaling. mPR signaling remains poorly understood. Here we show that the topology of mPRβ is similar to adiponectin receptors and opposite to that of G-protein-coupled receptors (GPCRs). Using Xenopus oocyte meiosis as a well-established physiological readout of nongenomic P4 signaling, we demonstrate that mPRβ signaling requires the adaptor protein APPL1 and the kinase Akt2. We further show that P4 induces clathrin-dependent endocytosis of mPRβ into signaling endosome, where mPR interacts transiently with APPL1 and Akt2 to induce meiosis. Our findings outline the early steps involved in mPR signaling and expand the spectrum of mPR signaling through the multitude of pathways involving APPL1. The steroid hormone progesterone mediates many physiological processes through either nuclear receptors that modulate gene expression, or membrane progesterone receptors (mPRs) that mediate non-genomic signaling. This study shows that non-genomic mPRβ signaling progresses through clathrin-dependent endocytosis into signaling endosomes where it interacts with and activates APPL1 and Akt2 to induce oocyte meiosis. [ABSTRACT FROM AUTHOR]

Introduction: Abnormalities in adipose tissue AdipoR1; adaptor protein, phosphotyrosine interaction, PH domain, and leucine zipper containing 1 (APPL1); GTPase Rab5; adiponectin; leptin; and visfatin in adults with obesity have been associated with metabolic disturbances. Objective: The objective of this study was to examine whether pediatric obesity disrupts elements of the adiponectin signaling pathway and GTPase Rab5 in adipose tissue. Methods: Primary adipocyte cultures of subcutaneous abdominal tissue were obtained from 96 lean and 66 children and adolescents with obesity (AO). AdipoR1, APPL1, and GTPase Rab5 mRNA levels were measured by RT-PCR and their protein content by Western immunoblotting. Serum total and high-molecular-weight adiponectin, leptin, leptin soluble receptor (sOB-R), and visfatin were measured by ELISA. Results: The mRNA expression and protein content of AdipoR1 and APPL1 did not differ significantly with obesity, age, or puberty. However, GTPase Rab5 protein was increased in the adipocytes of younger prepubertal children with obesity but decreased in AO. Leptin was increased in AO compared to lean adolescents (AL) and in older prepubertal lean (OPL) children and AL compared to younger prepubertal lean and obese children. sOB-R was higher in OPL children and in the AL and AO. Serum visfatin was increased in the younger prepubertal children and AO. Conclusions: In contrast to adults, obesity did not change the expression of AdipoR1 and APPL1 in cultured adipocytes from biopsies of subcutaneous abdominal adipose tissue of children and adolescents. Similar to adipose tissue studies in adults with obesity and metabolic dysfunction, the AO in our study showed reduced adipocyte GTPase Rab5 expression. [ABSTRACT FROM AUTHOR]

Adiponectin, an adipokine secreted by adipocytes, is a well-known homeostatic factor for regulating glucose levels, lipid metabolism, and insulin sensitivity through its anti-inflammatory, anti-fibrotic, and antioxidant effects. All these metabolic processes are mediated via two adiponectin receptors, AdipoR1 and AdipoR2. In addition, adiponectin is one of the hormones with the highest plasma concentrations. Weight loss or caloric restriction leads to increasing adiponectin levels, and this increase is associated with increased insulin sensitivity. Therefore, the adiponectin pathway can play a crucial role in the development of drugs to treat type 2 diabetes mellitus and other obesity-related diseases affected by insulin resistance like cancers or cardiovascular diseases. Adiponectin appears to increase insulin sensitivity by improving glucose and lipid metabolisms. The objective of this review is to analyze current knowledge concerning adiponectin and, in particular, its role in physiology and pathophysiology. [ABSTRACT FROM AUTHOR]

Adult olfactory neurogenesis plays critical roles in maintaining olfactory functions. Newly-generated neurons in the subventricular zone migrate to the olfactory bulb (OB) and determine olfactory discrimination, but the mechanisms underlying the regulation of olfactory neurogenesis remain unclear. Our previous study indicated the potential of APPL2 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 2) as a modulating factor for neurogenesis in the adult olfactory system. In the present study, we report how APPL2 affects neurogenesis in the OB and thereby mediates olfactory discrimination by using both in vitro neural stem cells (NSCs) and an in vivo animal model—APPL2 transgenic (Tg) mice. In the in vitro study, we found that APPL2 overexpression resulted in NSCs switching from neuronal differentiation to gliogenesis while APPL2 knockdown promoted neurogenesis. In the in vivo study, APPL2 Tg mice had a higher population of glial cells and dampened neuronal production in the olfactory system, including the corpus callosum, OB, and rostral migratory stream. Adult APPL2 Tg mice displayed impaired performance in olfactory discrimination tests compared with wild-type mice. Furthermore, we found that an interaction of APPL2 with Notch1 contributed to the roles of APPL2 in modulating the neurogenic lineage-switching and olfactory behaviors. In conclusion, APPL2 controls olfactory discrimination by switching the fate choice of NSCs via interaction with Notch1 signaling. [ABSTRACT FROM AUTHOR]

After confirmation of the presence of adiponectin (ADPN) receptors and intra-cellular binding proteins in coronary artery smooth muscle cells (VSMC), we tested the hypotheses that, in acute insulin resistance: (i) the activation/inactivation of metabolic and mitogenic insulin signaling pathways are inversely affected by ADPN and, (ii) changes in VSMC migration/proliferation rates correlate with signal activity/inactivity. In primary cultures of VSMC exposed to high glucose and palmitate plus insulin, the expression of PI-3 kinase (Akt and m-TOR), MAP-Kinase (Erk and p-38) molecules, and inflammatory markers (TLR-4 and IkB-α) were assessed with Western blot, in the absence/presence of AdipoRon (AR). Migration and proliferation rates were measured in similar experimental conditions. There were decreases of ~ 25% (p-Akt) and 40–60% (p-mTOR) expressions with high glucose/palmitate, which reversed when AR was added were. Elevations in p-Erk and p-p38 expressions were obliterated by AR. Although, no changes were detected with high glucose and palmitate, when AR was added, a decline in inflammatory activity was substantiated by a ~ 50% decrease in TLR-4 and 40–60% increase in IkBα expression. Functional assays showed 10–20% rise in VSMC proliferation with high glucose and palmitate, but addition of AR lead to 15–25% decline. The degree of VSMC migration was reduced with AR addition by ~ 15%, ~ 35% and 55%, in VSMC exposed to 5 mM, 25 mM glucose and 25 mM + 200 µM palmitate, respectively. Changes in intracellular molecular messaging in experiments mimicking acute insulin resistance suggest that anti-inflammatory and anti-atherogenic actions of ADPN in VSMC are mediated via insulin signaling pathways. [ABSTRACT FROM AUTHOR]