scholarly journals PPA1 Regulates Systemic Insulin Sensitivity by Maintaining Adipocyte Mitochondria Function as a Novel PPARγ Target Gene

2021 ◽  
Author(s):  
Ye Yin ◽  
Yangyang Wu ◽  
Xu Zhang ◽  
Yeting Zhu ◽  
Yue Sun ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Mitochondrial Function ◽  
Metabolic Disorders ◽  
Target Gene ◽  
Fat Body ◽  
Whole Body ◽  
Inorganic Pyrophosphatase ◽  
Severe Insulin Resistance ◽  
Adipose Tissue Development ◽  
First Time

<a>Downregulation of mitochondrial function in adipose tissue is considered as one important driver for the development of obesity-associated metabolic disorders. Inorganic Pyrophosphatase 1 (PPA1) is an enzyme catalyzes the hydrolysis of PPi to Pi, and is required for anabolism to take place in cells. Although alternation of PPA1 has been related to some diseases, the importance of PPA1 in metabolic syndromes has never been discussed before. In this study, we found that global PPA1 knockout mice (PPA1<sup>+/-</sup>) showed impaired glucose tolerance and severe insulin resistance under HFD feeding. In addition, impaired adipose tissue development and ectopic lipid accumulation were also observed. Conversely, overexpression of PPA1 in adipose tissue by AAV injection can partly reverse the metabolic disorders in PPA1<sup>+/-</sup> mice, suggesting that impaired adipose tissue function is responsible for the metabolic disorders observed in PPA1<sup>+/- </sup>mice. Mechanistic studies revealed that PPA1 acted as a PPARγ target gene to maintain mitochondrial function in adipocytes. Furthermore, specific knockdown of PPA1 in fat body of <i>Drosophila</i> led to impaired mitochondria morphology, decreased lipid storage, and made <i>Drosophila</i> more sensitive to starvation. In conclusion, for the first time, our findings demonstrated the importance of PPA1 in maintaining adipose tissue function and whole body metabolic homeostasis.</a>

scholarly journals PPA1 Regulates Systemic Insulin Sensitivity by Maintaining Adipocyte Mitochondria Function as a Novel PPARγ Target Gene

2021 ◽  
Author(s):  
Ye Yin ◽  
Yangyang Wu ◽  
Xu Zhang ◽  
Yeting Zhu ◽  
Yue Sun ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Mitochondrial Function ◽  
Metabolic Disorders ◽  
Target Gene ◽  
Fat Body ◽  
Whole Body ◽  
Inorganic Pyrophosphatase ◽  
Severe Insulin Resistance ◽  
Adipose Tissue Development ◽  
First Time

<a>Downregulation of mitochondrial function in adipose tissue is considered as one important driver for the development of obesity-associated metabolic disorders. Inorganic Pyrophosphatase 1 (PPA1) is an enzyme catalyzes the hydrolysis of PPi to Pi, and is required for anabolism to take place in cells. Although alternation of PPA1 has been related to some diseases, the importance of PPA1 in metabolic syndromes has never been discussed before. In this study, we found that global PPA1 knockout mice (PPA1<sup>+/-</sup>) showed impaired glucose tolerance and severe insulin resistance under HFD feeding. In addition, impaired adipose tissue development and ectopic lipid accumulation were also observed. Conversely, overexpression of PPA1 in adipose tissue by AAV injection can partly reverse the metabolic disorders in PPA1<sup>+/-</sup> mice, suggesting that impaired adipose tissue function is responsible for the metabolic disorders observed in PPA1<sup>+/- </sup>mice. Mechanistic studies revealed that PPA1 acted as a PPARγ target gene to maintain mitochondrial function in adipocytes. Furthermore, specific knockdown of PPA1 in fat body of <i>Drosophila</i> led to impaired mitochondria morphology, decreased lipid storage, and made <i>Drosophila</i> more sensitive to starvation. In conclusion, for the first time, our findings demonstrated the importance of PPA1 in maintaining adipose tissue function and whole body metabolic homeostasis.</a>

scholarly journals Codon-optimized FAM132b prevents diet-induced obesity by modulating adrenergic response and insulin action

2020 ◽  
Author(s):  
Zhengtang Qi ◽  
Jie Xia ◽  
Xiangli Xue ◽  
Wenbin Liu ◽  
Zhuochun Huang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Gene Transfer ◽  
Insulin Action ◽  
Metabolic Disorders ◽  
Codon Optimization ◽  
Whole Body ◽  
Therapeutic Effects ◽  
Glycemic Response ◽  
Adrenergic Response

AbstractFAM132b, also known as myonectin, has been identified as a myokine produced by exercise. It is a secreted protein precursor that belongs to the adipolin/erythroferrone family, and has hormone activity in circulation to regulate cellular iron homeostasis and lipid metabolism via unknown receptors. Here, adeno-associated viral vectors (AAV9) were engineered to induce overexpression of FAM132b with 2 codon mutations (A136T and P159A). Treatment of mice under high-fat diet feeding with FAM132b gene transfer resulted in marked reductions in body weight, fat depot, adipocytes size, glucose intolerance and insulin resistance. Moreover, FAM132b overproduction reduced glycemic response to epinephrine (EPI) in whole body and increased lipolytic response to EPI in adipose tissues. This adrenergic response of adipose tissue led to the result that gene transfer reduced glycogen utilization and increased fat consumption in skeletal muscle during exercise. FAM132b knockdown by shRNA significantly increased glycemic response to EPI in vivo and reduced adipocytes response to EPI and adipose tissue browning. Structural analysis suggested that FAM132b mutants delivered by AAV9 may form a weak bond with ADRB2, and potentially bind to insulin against insulin receptor by blocking the receptor binding sites on insulin B-chain. Our study underscores the potential of FAM132b gene therapy with codon optimization to treat obesity by modulating adrenergic response and interfering insulin action.SignificanceWe show here that AAV9-mediated expression of FAM132b with A136T and P159A is a safe and effective therapeutic strategy for improving glucose homeostasis. This is the first demonstration of a therapeutic effect on metabolic disorders in mice with FAM132b codon optimization. These therapeutic effects indicate that FAM132b gene transfer with selective codon mutants in vivo might be a valid therapy for diabetes that can be extended to other metabolic disorders.

scholarly journals Canine colostrum exosomes: Characterization and influence on the canine mesenchymal stem cell secretory profile and fibroblast anti-oxidative capacity.

2020 ◽  
Author(s):  
Antonio J Villatoro ◽  
María del Carmen Martín-Astorga ◽  
Cristina Alcoholado ◽  
José Becerra
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Adipose Tissue ◽  
Oxidative Capacity ◽  
Positive Expression ◽  
Species Activity ◽  
Adipose Tissue Development ◽  
Cell Mobilization ◽  
First Time

Abstract Background : Canine colostrum milk (CCM) is a specific secretion of the mammary gland that is fundamental for the survival of the newborn. CCM has many described components (immunoglobulins, proteins or fat), but its small vesicles, named exosomes, are largely unknown. Results : A characterization of CCM exosomes was performed. Exosomes were abundant in CCM and appeared with the characteristic cup-shaped morphology and well-defined round vesicles. The size distribution of exosomes was between 37 and 140 nm, and western blot analysis showed positive expression of specific exosomal markers. Proteomic analysis revealed a total of 826 proteins in exosome cargo. We also found that exosomes modified the proliferation and secretory profiles in canine mesenchymal stem cells derived from bone marrow (cBM-MSCs) and adipose tissue (cAd-MSCs). Additionally, CCM exosomes demonstrated a potent antioxidant effect on canine fibroblasts in culture. Conclusions : Our findings highlight, for the first time, the abundant presence of exosomes in CCM and their ability to interact with mesenchymal stem cells (MSCs). The addition of exosomes to two types of MSCs in culture resulted in specific secretory profiles with functions related to angiogenesis, migration and chemotaxis of immune cells. In particular, the cAd-MSCs secretory profile showed higher potential in adipose tissue development and neurogenesis, while cBM-MSC production was associated with immunity, cell mobilization and haematopoiesis. Finally, exosomes also presented antioxidant capacity on fibroblasts against reactive oxygen species activity within the cell, demonstrating their fundamental role in the development and maturation of dogs in the early stages of their life.

scholarly journals Peripheral Blood Mononuclear Cell Metabolism Acutely Adapted to Postprandial Transition and Mainly Reflected Metabolic Adipose Tissue Adaptations to a High-Fat Diet in Minipigs

Nutrients ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 1816 ◽  
Author(s):  
Yuchun Zeng ◽  
Jérémie David ◽  
Didier Rémond ◽  
Dominique Dardevet ◽  
Isabelle Savary-Auzeloux ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Peripheral Blood ◽  
Time Course ◽  
Mononuclear Cells ◽  
Cell Metabolism ◽  
Whole Body ◽  
High Fat ◽  
Short Term ◽  
Peripheral Blood Mononuclear ◽  
First Time

Although peripheral blood mononuclear cells (PBMCs) are widely used as a valuable tool able to provide biomarkers of health and diseases, little is known about PBMC functional (biochemistry-based) metabolism, particularly following short-term nutritional challenges. In the present study, the metabolic capacity of minipig PBMCs to respond to nutritional challenges was explored at the biochemical and molecular levels. The changes observed in enzyme activities following a control test meal revealed that PBMC metabolism is highly reactive to the arrival of nutrients and hormones in the circulation. The consumption, for the first time, of a high fat–high sucrose (HFHS) meal delayed or sharply reduced most of the observed postprandial metabolic features. In a second experiment, minipigs were subjected to two-month HFHS feeding. The time-course follow-up of metabolic changes in PBMCs showed that most of the adaptations to the new diet took place during the first week. By comparing metabolic (biochemical and molecular) PMBC profiles to those of the liver, skeletal muscle, and adipose tissue, we concluded that although PBMCs conserved common features with all of them, their response to the HFHS diet was closely related to that of the adipose tissue. As a whole, our results show that PBMC metabolism, particularly during short-term (postprandial) challenges, could be used to evaluate the whole-body metabolic status of an individual. This could be particularly interesting for early diagnosis of metabolic disease installation, when fasting clinical analyses fail to diagnose the path towards the pathology.

scholarly journals Phenotypic Heterogeneity in Body Fat Distribution in Patients with Congenital Generalized Lipodystrophy Caused by Mutations in the AGPAT2 or Seipin Genes

2003 ◽  
Vol 88 (11) ◽  
pp. 5433-5437 ◽  
Author(s):  
Vinaya Simha ◽  
Abhimanyu Garg
Keyword(s):  
Adipose Tissue ◽  
Body Fat ◽  
Autosomal Recessive ◽  
Acanthosis Nigricans ◽  
Fat Distribution ◽  
Body Fat Distribution ◽  
Whole Body ◽  
Severe Insulin Resistance ◽  
Congenital Generalized Lipodystrophy ◽  
Chromosome 9Q34

Abstract Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive syndrome characterized by extreme paucity of adipose tissue since birth, acanthosis nigricans, severe insulin resistance, marked hypertriglyceridemia, and early-onset diabetes mellitus. Recently, we reported mutations in the 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) gene in CGL pedigrees linked to chromosome 9q34 (CGL1 subtype), and mutations in the Seipin gene were reported in pedigrees linked to chromosome 11q13 (CGL2 subtype). Whether the two subtypes have differences in body fat distribution has not been investigated. We, therefore, compared whole-body adipose tissue distribution by magnetic resonance imaging in 10 CGL patients, of whom seven (six females, one male) had CGL1 and three (two males, one female) had CGL2. Both subtypes had marked lack of metabolically active adipose tissue located at most sc, intermuscular, bone marrow, intraabdominal, and intrathoracic regions. Paucity of mechanical adipose tissue in the palms, soles, orbits, scalp, and periarticular regions was noted in CGL2, whereas it was well preserved in CGL1 patients. We conclude that CGL patients with Seipin mutations have a more severe lack of body fat, which affects both metabolically active and mechanical adipose tissue, compared with patients with mutations in the AGPAT2 gene.

Cyanidin-3-glucoside increases whole body energy metabolism by upregulating brown adipose tissue mitochondrial function

2017 ◽  
Vol 61 (11) ◽  
pp. 1700261 ◽  
Author(s):  
Yilin You ◽  
Xiaoxue Yuan ◽  
Xiaomeng Liu ◽  
Chen Liang ◽  
Minghui Meng ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Metabolism ◽  
Brown Adipose Tissue ◽  
Mitochondrial Function ◽  
Whole Body ◽  
Brown Adipose ◽  
Body Energy

scholarly journals Canine colostrum exosomes: characterization and influence on canine mesenchymal stem cell secretory profile and fibroblast anti-oxidative capacity

2020 ◽  
Author(s):  
Antonio J Villatoro ◽  
María del Carmen Martín-Astorga ◽  
Cristina Alcoholado ◽  
José Becerra
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Adipose Tissue ◽  
Oxidative Capacity ◽  
Positive Expression ◽  
Species Activity ◽  
Adipose Tissue Development ◽  
Cell Mobilization ◽  
First Time

Abstract Background: Canine colostrum milk (CCM) is a specific secretion of the mammary gland fundamental for the survival of the newborn. It has many described components (immunoglobulins, proteins or fat), but small vesicles named exosomes are largely unknown. Results: A characterization of the CCM exosomes has been performed. Exosome concentrations were abundant in CCM and appeared with characteristic cup-shaped morphology and well-defined round vesicles. Their size distribution was between 37−140 nm and western blot analysis showed positive expression of specific exosomal markers. Proteomic analysis revealed a total of 826 proteins in exosomes cargo. We also found that exosomes modified proliferation and secretory profiles in canine mesenchymal stem cells derived from bone marrow (cBM-MSCs) and adipose tissue (cAd-MSCs). Besides, CCM exosomes demonstrated a potent antioxidant effect on canine fibroblasts in culture. Conclusions: Our findings highlight, for the first time, the abundant presence of exosomes in CCM and their ability to interact with mesenchymal stem cells (MSCs). The addition of exosomes to the two types of MSCs in culture resulted in specific secretory profiles with functions related to angiogenesis, migration and chemotaxis of immune cells. In particular, the cAd-MSCs secretory profile showed a higher potential in adipose tissue development and neurogenesis, while cBM-MSCs production was associated with immunity, cell mobilization and hematopoiesis. Finally, exosomes also presented antioxidant capacity on fibroblasts against reactive oxygen species activity within the cell, demonstrating a fundamental role in the development and maturation of the puppy in the early stages of its life.

scholarly journals TORC1 modulation in adipose tissue is required for organismal adaptation to hypoxia in Drosophila

2018 ◽  
Author(s):  
Byoungchun Lee ◽  
Elizabeth C. Barretto ◽  
Savraj S. Grewal
Keyword(s):  
Adipose Tissue ◽  
Normal Development ◽  
Fat Body ◽  
Lipid Storage ◽  
Hypoxia Tolerance ◽  
Whole Body ◽  
Adaptation To Hypoxia ◽  
Low Oxygen ◽  
Body Development ◽  
Drosophila Larvae

ABSTRACTAnimals often develop in conditions where environmental conditions such as food, oxygen and temperature fluctuate. The ability to adapt their metabolism to these fluctuations is important to ensure normal development and viability. In most animals, low oxygen (hypoxia) is deleterious, however some animals can alter their physiology to thrive under hypoxia. Here we show that TORC1 modulation in adipose tissue is required for organismal adaptation to hypoxia in Drosophila. We find that hypoxia rapidly suppresses TORC1 kinase signalling in Drosophila larvae via TSC-mediated inhibition of Rheb. We show that this hypoxia-mediated inhibition of TORC1 specifically in the larval fat body is essential for viable development to adulthood. Moreover, we find that these effects of TORC1 inhibition on hypoxia tolerance are mediated through remodeling of fat body lipid droplets and lipid storage. These studies identify the larval adipose tissue as a key hypoxia sensing tissue that coordinates whole-body development and survival to changes in environmental oxygen by modulating TORC1 and lipid storage.

scholarly journals Adipose-Derived Exosomes as Possible Players in the Development of Insulin Resistance

2021 ◽  
Vol 22 (14) ◽  
pp. 7427
Author(s):  
Arkadiusz Żbikowski ◽  
Agnieszka Błachnio-Zabielska ◽  
Mauro Galli ◽  
Piotr Zabielski
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Metabolic Disorders ◽  
Biologically Active ◽  
Whole Body ◽  
Secretory Function ◽  
Endocrine Organ ◽  
Actual Knowledge ◽  
Whole Body Metabolism

Adipose tissue (AT) is an endocrine organ involved in the management of energy metabolism via secretion of adipokines, hormones, and recently described secretory microvesicles, i.e., exosomes. Exosomes are rich in possible biologically active factors such as proteins, lipids, and RNA. The secretory function of adipose tissue is affected by pathological processes. One of the most important of these is obesity, which triggers adipose tissue inflammation and adversely affects the release of beneficial adipokines. Both processes may lead to further AT dysfunction, contributing to changes in whole-body metabolism and, subsequently, to insulin resistance. According to recent data, changes within the production, release, and content of exosomes produced by AT may be essential to understand the role of adipose tissue in the development of metabolic disorders. In this review, we summarize actual knowledge about the possible role of AT-derived exosomes in the development of insulin resistance, highlighting methodological challenges and potential gains resulting from exosome studies.

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