scholarly journals Adipose tissue hyaluronan production improves systemic glucose homeostasis and primes adipocytes for CL 316,243-stimulated lipolysis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yi Zhu ◽  
Na Li ◽  
Mingyang Huang ◽  
Mason Bartels ◽  
Sophie Dogné ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Adrenergic Stimulation ◽  
Synthesis Inhibitor ◽  
Transgenic Mouse Line ◽  
Diet Induced Obesity ◽  
Cl 316,243 ◽  
High Sucrose Diet ◽  
Hyaluronan Synthase 2

AbstractPlasma hyaluronan (HA) increases systemically in type 2 diabetes (T2D) and the HA synthesis inhibitor, 4-Methylumbelliferone, has been proposed to treat the disease. However, HA is also implicated in normal physiology. Therefore, we generated a Hyaluronan Synthase 2 transgenic mouse line, driven by a tet-response element promoter to understand the role of HA in systemic metabolism. To our surprise, adipocyte-specific overproduction of HA leads to smaller adipocytes and protects mice from high-fat-high-sucrose-diet-induced obesity and glucose intolerance. Adipocytes also have more free glycerol that can be released upon beta3 adrenergic stimulation. Improvements in glucose tolerance were not linked to increased plasma HA. Instead, an HA-driven systemic substrate redistribution and adipose tissue-liver crosstalk contributes to the systemic glucose improvements. In summary, we demonstrate an unexpected improvement in glucose metabolism as a consequence of HA overproduction in adipose tissue, which argues against the use of systemic HA synthesis inhibitors to treat obesity and T2D.

Targeting PLD2 in adipocytes augments adaptive thermogenesis by improving mitochondrial quality and quantity in mice

2021 ◽  
Vol 219 (2) ◽  
Author(s):  
Hyung Sik Kim ◽  
Min Young Park ◽  
Nam Joo Yun ◽  
Hye Sun Go ◽  
Mi Young Kim ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Uncoupling Protein ◽  
Specific Inhibitor ◽  
Adaptive Thermogenesis ◽  
Diet Induced Obesity ◽  
Diet Induced Thermogenesis ◽  
And Migration

Phospholipase D (PLD)2 via its enzymatic activity regulates cell proliferation and migration and thus is implicated in cancer. However, the role of PLD2 in obesity and type 2 diabetes has not previously been investigated. Here, we show that during diet-induced thermogenesis and obesity, levels of PLD2 but not PLD1 in adipose tissue are inversely related with uncoupling protein 1, a key thermogenic protein. We demonstrate that the thermogenic program in adipose tissue is significantly augmented in mice with adipocyte-specific Pld2 deletion or treated with a PLD2-specific inhibitor and that these mice are resistant to high fat diet–induced obesity, glucose intolerance, and insulin resistance. Mechanistically, we show that Pld2 deletion in adipose tissue or PLD2 pharmacoinhibition acts via p62 to improve mitochondrial quality and quantity in adipocytes. Thus, PLD2 inhibition is an attractive therapeutic approach for obesity and type 2 diabetes by resolving defects in diet-induced thermogenesis.

scholarly journals Role of Muscle c-Jun NH2-Terminal Kinase 1 in Obesity-Induced Insulin Resistance

2009 ◽  
Vol 30 (1) ◽  
pp. 106-115 ◽  
Author(s):  
Guadalupe Sabio ◽  
Norman J. Kennedy ◽  
Julie Cavanagh-Kyros ◽  
Dae Young Jung ◽  
Hwi Jin Ko ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Akt Activation ◽  
Peripheral Insulin Resistance ◽  
Diet Induced Obesity

ABSTRACT Obesity caused by feeding of a high-fat diet (HFD) is associated with an increased activation of c-Jun NH2-terminal kinase 1 (JNK1). Activated JNK1 is implicated in the mechanism of obesity-induced insulin resistance and the development of metabolic syndrome and type 2 diabetes. Significantly, Jnk1 − / − mice are protected against HFD-induced obesity and insulin resistance. Here we show that an ablation of the Jnk1 gene in skeletal muscle does not influence HFD-induced obesity. However, muscle-specific JNK1-deficient (MKO) mice exhibit improved insulin sensitivity compared with control wild-type (MWT) mice. Thus, insulin-stimulated AKT activation is suppressed in muscle, liver, and adipose tissue of HFD-fed MWT mice but is suppressed only in the liver and adipose tissue of MKO mice. These data demonstrate that JNK1 in muscle contributes to peripheral insulin resistance in response to diet-induced obesity.

scholarly journals RGC32 deficiency protects against high-fat diet-induced obesity and insulin resistance in mice

2014 ◽  
Vol 224 (2) ◽  
pp. 127-137 ◽  
Author(s):  
Xiao-Bing Cui ◽  
Jun-Na Luan ◽  
Jianping Ye ◽  
Shi-You Chen
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Tolerance Test ◽  
High Fat ◽  
Diet Induced Obesity

Obesity is an important independent risk factor for type 2 diabetes, cardiovascular diseases and many other chronic diseases. Adipose tissue inflammation is a critical link between obesity and insulin resistance and type 2 diabetes and a contributor to disease susceptibility and progression. The objective of this study was to determine the role of response gene to complement 32 (RGC32) in the development of obesity and insulin resistance. WT and RGC32 knockout (Rgc32−/− (Rgcc)) mice were fed normal chow or high-fat diet (HFD) for 12 weeks. Metabolic, biochemical, and histologic analyses were performed. 3T3-L1 preadipocytes were used to study the role of RGC32 in adipocytes in vitro. Rgc32−/− mice fed with HFD exhibited a lean phenotype with reduced epididymal fat weight compared with WT controls. Blood biochemical analysis and insulin tolerance test showed that RGC32 deficiency improved HFD-induced dyslipidemia and insulin resistance. Although it had no effect on adipocyte differentiation, RGC32 deficiency ameliorated adipose tissue and systemic inflammation. Moreover, Rgc32−/− induced browning of adipose tissues and increased energy expenditure. Our data indicated that RGC32 plays an important role in diet-induced obesity and insulin resistance, and thus it may serve as a potential novel drug target for developing therapeutics to treat obesity and metabolic disorders.

scholarly journals Key Role of STAT4 Deficiency in the Hematopoietic Compartment in Insulin Resistance and Adipose Tissue Inflammation

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Anca D. Dobrian ◽  
Kaiwen Ma ◽  
Lindsey M. Glenn ◽  
Margaret A. Hatcher ◽  
Bronson A. Haynes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Bone Marrow Cells ◽  
Cd8 Cells ◽  
Diet Induced Obesity ◽  
Hematopoietic Lineage ◽  
Islet Inflammation ◽  
Visceral Adipose

Visceral adipose tissue (AT) inflammation is linked to the complications of obesity, including insulin resistance (IR) and type 2 diabetes. Recent data from our lab showed that germline deficiency in STAT4 reduces inflammation and improves IR in obese mice. The objective of this study was to determine the contribution of selective STAT4 deficiency in subsets of hematopoietic cells to IR and AT inflammation. To determine the contribution of hematopoietic lineage, we sublethally irradiated Stat4−/−C57Bl6 mice and reconstituted them with bone marrow cells (BMC) from Stat4+/+C57Bl6 congenic donors. We also established the contribution of selective STAT4 deficiency in CD4+ or CD8+ T cells using adoptive transfer in Rag1−/− mice. All mice received a HFD for 15 weeks (n=7–12 mice/group). BMC that expressed STAT4 induced increases in glucose intolerance and IR compared to STAT4-deficient cells. Also, AT inflammation was increased and the numbers of CD8+ cells infiltrating AT were higher in mice with STAT4 expressing BMC. Studies in Rag1−/− mice further confirmed the prominent role of CD8+ cells expressing STAT4 in insulin resistance and AT and islet inflammation. Collectively our results show specific and dominant contribution of STAT4 in the hematopoietic compartment to metabolic health and inflammation in diet-induced obesity.

scholarly journals Improvement of obesity-associated disorders by a small-molecule drug targeting mitochondria of adipose tissue macrophages

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yawei Wang ◽  
Binlin Tang ◽  
Lei Long ◽  
Peng Luo ◽  
Wei Xiang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Oxidative Phosphorylation ◽  
Near Infrared ◽  
Mitochondrial Metabolism ◽  
Diet Induced Obesity ◽  
Adipose Tissue Macrophages ◽  
Inflammatory Activation ◽  
Treatment Of Obesity ◽  
Pharmaceutical Agents

AbstractPro-inflammatory activation of adipose tissue macrophages (ATMs) is causally linked to obesity and obesity-associated disorders. A number of studies have demonstrated the crucial role of mitochondrial metabolism in macrophage activation. However, there is a lack of pharmaceutical agents to target the mitochondrial metabolism of ATMs for the treatment of obesity-related diseases. Here, we characterize a near-infrared fluorophore (IR-61) that preferentially accumulates in the mitochondria of ATMs and has a therapeutic effect on diet-induced obesity as well as obesity-associated insulin resistance and fatty liver. IR-61 inhibits the classical activation of ATMs by increasing mitochondrial complex levels and oxidative phosphorylation via the ROS/Akt/Acly pathway. Taken together, our findings indicate that specific enhancement of ATMs oxidative phosphorylation improves chronic inflammation and obesity-related disorders. IR-61 might be an anti-inflammatory agent useful for the treatment of obesity-related diseases by targeting the mitochondria of ATMs.

scholarly journals Adipose tissue inflammation and metabolic dysfunction: a clinical perspective

2013 ◽  
Vol 15 (1) ◽  
Author(s):  
Charmaine S. Tam ◽  
Leanne M. Redman
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Low Grade ◽  
Metabolic Dysfunction ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Proinflammatory Mediators ◽  
Low Grade Inflammation

AbstractObesity is characterized by a state of chronic low-grade inflammation due to increased immune cells, specifically infiltrated macrophages into adipose tissue, which in turn secrete a range of proinflammatory mediators. This nonselective low-grade inflammation of adipose tissue is systemic in nature and can impair insulin signaling pathways, thus, increasing the risk of developing insulin resistance and type 2 diabetes. The aim of this review is to provide an update on clinical studies examining the role of adipose tissue in the development of obesity-associated complications in humans. We will discuss adipose tissue inflammation during different scenarios of energy imbalance and metabolic dysfunction including obesity and overfeeding, weight loss by calorie restriction or bariatric surgery, and conditions of insulin resistance (diabetes, polycystic ovarian syndrome).

scholarly journals Adipocytes, Innate Immunity and Obesity: A Mini-Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Alecia M. Blaszczak ◽  
Anahita Jalilvand ◽  
Willa A. Hsueh
Keyword(s):  
Adipose Tissue ◽  
Immune System ◽  
Immune Cells ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Lymphoid Cells ◽  
Innate Immune Cells ◽  
Adaptive Immune

The role of adipose tissue (AT) inflammation in obesity and its multiple related-complications is a rapidly expanding area of scientific interest. Within the last 30 years, the role of the adipocyte as an endocrine and immunologic cell has been progressively established. Like the macrophage, the adipocyte is capable of linking the innate and adaptive immune system through the secretion of adipokines and cytokines; exosome release of lipids, hormones, and microRNAs; and contact interaction with other immune cells. Key innate immune cells in AT include adipocytes, macrophages, neutrophils, and innate lymphoid cells type 2 (ILC2s). The role of the innate immune system in promoting adipose tissue inflammation in obesity will be highlighted in this review. T cells and B cells also play important roles in contributing to AT inflammation and are discussed in this series in the chapter on adaptive immunity.

scholarly journals Inflammation of adipose tissue. Part 2. Pathogenetic role in type 2 diabetes mellitus

2009 ◽  
Vol 55 (5) ◽  
pp. 43-48 ◽  
Author(s):  
V Shvarts
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Adipose Tissue ◽  
Cell Function ◽  
Signal Pathway ◽  
Insulin Signal ◽  
Kinase Cascade

This review deals with the role of adipose tissue inflammation (ATI) in the development of type 2 diabetes mellitus (DM2). ATI is regarded as a link between obesity and DM2. The review illustrates the involvement of main adipokines in pathogenesis of DM2 and provides a detailed description of such factors as impaired adiponectin and stimulation of cytokine production responsible for metabolic disorders, activation of lipolysis, in adipocytes, increased fatty acid and triglyceride levels, suppression of insulin activity at the receptor and intracellular levels. Adipokines, in the first place cytokines, act on the insulin signal pathway and affect the intracellular inflammatory kinase cascade. At the intercellular level, ATI stimulates JNK and IKK-beta/kB responsible for the development of insulin resistance via such mechanisms as activation of cytokine secretion in the adipose tissue, oxidative stress, and induction of endoplasmic reticulum enzymes. The key role of JNK and IKK-beta/kB in the inhibition of the insulin signal pathway is mediated through inactivation of insulin receptor substrate 1. Also, it is shown that ATI modulates B-cell function and promotes progressive reduction of insulin secretion.

scholarly journals Functional Interactomes of Genes Showing Association with Type-2 Diabetes and Its Intermediate Phenotypic Traits Point towards Adipo-Centric Mechanisms in Its Pathophysiology

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 601
Author(s):  
Aditya Saxena ◽  
Nitin Wahi ◽  
Anshul Kumar ◽  
Sandeep Kumar Mathur
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Network Analysis ◽  
Potential Role ◽  
Phenotypic Traits ◽  
Protein Protein Interaction ◽  
Cellular Processes ◽  
Antidiabetic Treatment

The pathogenic mechanisms causing type 2 diabetes (T2D) are still poorly understood; a greater awareness of its causation can lead to the development of newer and better antidiabetic drugs. In this study, we used a network-based approach to assess the cellular processes associated with protein–protein interaction subnetworks of glycemic traits—HOMA-β and HOMA-IR. Their subnetworks were further analyzed in terms of their overlap with the differentially expressed genes (DEGs) in pancreatic, muscle, and adipose tissue in diabetics. We found several DEGs in these tissues showing an overlap with the HOMA-β subnetwork, suggesting a role of these tissues in β-cell failure. Many genes in the HOMA-IR subnetwork too showed an overlap with the HOMA-β subnetwork. For understanding the functional theme of these subnetworks, a pathway-to-pathway complementary network analysis was done, which identified various adipose biology-related pathways, containing genes involved in both insulin secretion and action. In conclusion, network analysis of genes showing an association between T2D and its intermediate phenotypic traits suggests their potential role in beta cell failure. These genes enriched the adipo-centric pathways and were expressed in both pancreatic and adipose tissue and, therefore, might be one of the potential targets for future antidiabetic treatment.

scholarly journals Phosphocholine accumulation and PHOSPHO1 depletion promote adipose tissue thermogenesis

2020 ◽  
Vol 117 (26) ◽  
pp. 15055-15065 ◽  
Author(s):  
Mengxi Jiang ◽  
Tony E. Chavarria ◽  
Bingbing Yuan ◽  
Harvey F. Lodish ◽  
Nai-Jia Huang
Keyword(s):  
Adipose Tissue ◽  
Negative Regulator ◽  
Brown Adipocytes ◽  
Diet Induced Obesity ◽  
The Metabolic Syndrome ◽  
Brown Adipose ◽  
Cold Tolerant ◽  
Functional Relevance ◽  
Hydrolysis Of

Phosphocholine phosphatase-1 (PHOSPHO1) is a phosphocholine phosphatase that catalyzes the hydrolysis of phosphocholine (PC) to choline. Here we demonstrate that the PHOSPHO1 transcript is highly enriched in mature brown adipose tissue (BAT) and is further induced by cold and isoproterenol treatments of BAT and primary brown adipocytes. In defining the functional relevance of PHOPSPHO1 in BAT thermogenesis and energy metabolism, we show that PHOSPHO1 knockout mice are cold-tolerant, with higher expression of thermogenic genes in BAT, and are protected from high-fat diet-induced obesity and development of insulin resistance. Treatment of mice with the PHOSPHO1 substrate phosphocholine is sufficient to induce cold tolerance, thermogenic gene expression, and allied metabolic benefits. Our results reveal a role of PHOSPHO1 as a negative regulator of BAT thermogenesis, and inhibition of PHOSPHO1 or enhancement of phosphocholine represent innovative approaches to manage the metabolic syndrome.

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