scholarly journals Impaired mRNA splicing and proteostasis in preadipocytes in obesity-related metabolic disease

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Julia Sánchez-Ceinos ◽  
Rocío Guzmán-Ruiz ◽  
Oriol Alberto Rangel-Zuñiga ◽  
Jaime López-Alcalá ◽  
Elena Moreno-Caño ◽  
...  
Keyword(s):  
Metabolic Disease ◽  
Adipose Tissue ◽  
Adipocyte Differentiation ◽  
Tissue Expansion ◽  
Mrna Splicing ◽  
Metabolic Disturbances ◽  
Preadipocyte Differentiation ◽  
Related Proteins ◽  
Splicing Patterns

Preadipocytes are crucial for healthy adipose tissue expansion. Preadipocyte differentiation is altered in obese individuals, which has been proposed to contribute to obesity-associated metabolic disturbances. Here, we aimed at identifying the pathogenic processes underlying impaired adipocyte differentiation in obese individuals with insulin resistance (IR)/type 2 diabetes (T2D). We report that down-regulation of a key member of the major spliceosome, PRFP8/PRP8, as observed in IR/T2D preadipocytes from subcutaneous (SC) fat, prevented adipogenesis by altering both the expression and splicing patterns of adipogenic transcription factors and lipid droplet-related proteins, while adipocyte differentiation was restored upon recovery of PRFP8/PRP8 normal levels. Adipocyte differentiation was also compromised under conditions of endoplasmic reticulum (ER)-associated protein degradation (ERAD) hyperactivation, as occurs in SC and omental (OM) preadipocytes in IR/T2D obesity. Thus, targeting mRNA splicing and ER proteostasis in preadipocytes could improve adipose tissue function and thus contribute to metabolic health in obese individuals.

scholarly journals Impaired mRNA splicing and proteostasis in preadipocytes in obesity-related metabolic disease

2021 ◽  
Author(s):  
Julia Sánchez-Ceinos ◽  
Rocío Guzmán-Ruiz ◽  
Oriol A. Rangel-Zúñiga ◽  
Elena Moreno-Caño ◽  
Mercedes del Río-Moreno ◽  
...  
Keyword(s):  
Metabolic Disease ◽  
Adipose Tissue ◽  
Adipocyte Differentiation ◽  
Tissue Expansion ◽  
Mrna Splicing ◽  
Metabolic Disturbances ◽  
Preadipocyte Differentiation ◽  
Related Proteins ◽  
Splicing Patterns

AbstractPreadipocytes are crucial for healthy adipose tissue expansion. Preadipocyte differentiation is altered in obese individuals, which has been proposed to contribute to obesity-associated metabolic disturbances. Here, we demonstrate that impaired alternative splicing and dysregulated endoplasmic reticulum (ER)-associated protein degradation (ERAD) represent marker pathways of dysfunctional preadipocytes in obese individuals with insulin resistance (IR)/type 2 diabetes (T2D). Down-regulation of a key member of the major spliceosome, PRFP8/PRP8, as observed in IR/T2D preadipocytes from subcutaneous (SC) fat, prevented adipogenesis by altering both the expression and splicing patterns of adipogenic transcription factors and lipid droplet-related proteins, while adipocyte differentiation was restored upon recovery of PRFP8/PRP8 normal levels. Adipocyte differentiation was also compromised under conditions of ERAD hyperactivation, as occurs in SC and omental (OM) preadipocytes in IR/T2D obesity. Thus, targeting mRNA splicing and ER proteostasis in preadipocytes could improve adipose tissue function and thus contribute to metabolic health in obese individuals.

scholarly journals Mitigation of the Adverse Consequences of Nutrient Excess on the Kidney: A Unified Hypothesis to Explain the Renoprotective Effects of Sodium-Glucose Cotransporter 2 Inhibitors

2020 ◽  
Vol 51 (4) ◽  
pp. 289-293 ◽  
Author(s):  
Milton Packer
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Renin Angiotensin System ◽  
Tissue Expansion ◽  
Adenosine Monophosphate ◽  
Sglt2 Inhibitors ◽  
Sirtuin 1 ◽  
Glomerular Hyperfiltration ◽  
Sodium Glucose Cotransporter

The 2 most common causes of chronic kidney disease worldwide (type 2 diabetes and obesity) are states of nutrient excess, suggesting that fuel overabundance leads to deleterious effects on the structure and function of the kidneys. Three pathophysiological pathways may potentially explain this linkage. First, both obesity and type 2 diabetes are characterized by glomerular hyperfiltration, which may result from increased proximal tubular reabsorption of sodium (due to enhanced glucose and sodium transport) coupled with activation of the renin-angiotensin system. Second, both obesity and type 2 diabetes are characterized by adipose tissue expansion and inflammation, followed by the augmented synthesis and release of lipid intermediates and proinflammatory adipocytokines that can have deleterious effects on the kidney. Third, states of nutrient excess cause a diminution in the activation of the energy sensors, sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK). The result is a suppression of autophagy, a lysosomal degradative pathway that is responsible for the clearance of damaged organelles that are an important source of oxidative and endoplasmic reticulum stress and inflammation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors induces a transcriptional paradigm that mimics fasting, which leads to the amelioration of glomerular hyperfiltration and adipose tissue inflammation as well as augmentation of AMPK/SIRT1 signaling and autophagy, thereby acting to mute organellar and cellular stress in the kidney. Therefore, SGLT2 inhibitors are positioned to antagonize all 3 pathways by which nutrient excess can lead to nephropathy.

scholarly journals Adipose Tissue-Derived Signatures for Obesity and Type 2 Diabetes: Adipokines, Batokines and MicroRNAs

2019 ◽  
Vol 8 (6) ◽  
pp. 854 ◽  
Author(s):  
Min-Woo Lee ◽  
Mihye Lee ◽  
Kyoung-Jin Oh
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Metabolic Disturbances ◽  
Endocrine Organ ◽  
Brown Adipose ◽  
Exosomal Mirnas ◽  
Exosomal Mirna

Obesity is one of the main risk factors for type 2 diabetes mellitus (T2DM). It is closely related to metabolic disturbances in the adipose tissue that primarily functions as a fat reservoir. For this reason, adipose tissue is considered as the primary site for initiation and aggravation of obesity and T2DM. As a key endocrine organ, the adipose tissue communicates with other organs, such as the brain, liver, muscle, and pancreas, for the maintenance of energy homeostasis. Two different types of adipose tissues—the white adipose tissue (WAT) and brown adipose tissue (BAT)—secrete bioactive peptides and proteins, known as “adipokines” and “batokines,” respectively. Some of them have beneficial anti-inflammatory effects, while others have harmful inflammatory effects. Recently, “exosomal microRNAs (miRNAs)” were identified as novel adipokines, as adipose tissue-derived exosomal miRNAs can affect other organs. In the present review, we discuss the role of adipose-derived secretory factors—adipokines, batokines, and exosomal miRNA—in obesity and T2DM. It will provide new insights into the pathophysiological mechanisms involved in disturbances of adipose-derived factors and will support the development of adipose-derived factors as potential therapeutic targets for obesity and T2DM.

scholarly journals Pathogenic obesity and nutraceuticals

2011 ◽  
Vol 70 (4) ◽  
pp. 426-438 ◽  
Author(s):  
K. P. Conroy ◽  
I. M. Davidson ◽  
M. Warnock
Keyword(s):  
Adipose Tissue ◽  
Plasma Concentrations ◽  
Tissue Expansion ◽  
Overweight And Obesity ◽  
Low Grade ◽  
Plasma Nefa ◽  
Positive Effects ◽  
Adipocyte Cell ◽  
Randomised Controlled

Over a decade of intense research in the field of obesity has led to the knowledge that chronic, excessive adipose tissue expansion leads to an increase in the risk for CVD, type 2 diabetes mellitus and cancer. This is primarily thought to stem from the low-grade, systemic inflammatory response syndrome that characterises adipose tissue in obesity, and this itself is thought to arise from the complex interplay of factors including metabolic endotoxaemia, increased plasma NEFA, hypertrophic adipocytes and localised hypoxia. Plasma concentrations of vitamins and antioxidants are lower in obese individuals than in the non-obese, which is hypothesised to negatively affect the development of inflammation and disease in obesity. This paper provides a review of the current literature investigating the potential of nutraceuticals to ameliorate the development of oxidative stress and inflammation in obesity, thereby limiting the onset of obesity complications. Research has found nutraceuticals able to positively modulate the activity of adipocyte cell lines and further positive effects have been found in other aspects of pathogenic obesity. While their ability to affect weight loss is still controversial, it is clear that they have a great potential to reverse the development of overweight and obesity-related comorbidities; this, however, still requires much research especially that utilising well-structured randomised controlled trials.

scholarly journals CREBRF p.Arg457Gln Promotes Obesity and Improves Insulin Sensitivity by Promoting Preadipocyte Differentiation and Reducing Oxidative Metabolism in Gene-modified Pig Models

2021 ◽  
Author(s):  
Yingying Li ◽  
Hai Wang ◽  
Yuan Liao ◽  
Quanmei Yan ◽  
Zhen Ouyang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Oxidative Metabolism ◽  
Reactive Oxygen ◽  
Oxidative Capacity ◽  
Oxygen Species ◽  
Preadipocyte Differentiation ◽  
Human Mutation

Abstract Obesity is one of the most important risk factors for type 2 diabetes (T2DM). The CREBRF missense allele of rs373863828 (p.Arg457Gln) is associated with increased body mass index (BMI), yet reduced risk of T2DM in people with Pacific ancestry. To investigate the functional consequences of the CREBRF variant, we introduced the corresponding human mutation p.Arg457Gln into porcine genome by using a CRISPR/Cas9-mediated homologous recombination (HR)-dependent approach. The CREBRF p.Arg457Gln pig models displayed dramatically increased fat deposition, yet improved sensitivity to insulin. Transcriptome and metabolome analyses of subcutaneous white adipose tissues showed that the CREBRF p.Arg457Gln mutation promoted preadipocyte differentiation, which indicated that obesity was caused by increased number (hyperplasia) rather than size (hypertrophy) of adipocytes. In addition, the oxidative capacity decreased in the adipose tissue of pigs with CREBRF p.Arg457Gln variant. The pre-oxidative metabolite content (4-HNE and MDA) significantly decreased, while activity of antioxidant enzymes (GPX, SOD, and CAT) increased, thereby repressing oxidative metabolism of adipose tissue and reducing level of reactive oxygen species (ROS). The low reactive oxygen species could prevent insulin resistance and reduce risk of obesity-induced type 2 diabetes. This study provides further mechanistic insights into favourable adiposity resulting from CREBRF p.Arg457Gln.

scholarly journals Brown and Beige Fat: Therapeutic Potential in Obesity

2014 ◽  
Vol 6 (2) ◽  
pp. 65
Author(s):  
Anna Meiliana ◽  
Andi Wijaya
Keyword(s):  
Metabolic Disease ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Therapeutic Effects ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
Beige Adipocytes ◽  
Beige Fat ◽  
Adipose Organ

BACKGROUND: The epidemic of obesity and type 2 diabetes presents a serious challenge to scientific and biomedical communities worldwide. There has been an upsurge of interest in the adipocyte coincident with the onset of the obesity epidemic and the realization that adipose tissue plays a major role in the regulation of metabolic function.CONTENT: Adipose tissue, best known for its role in fat storage, can also suppress weight gain and metabolic disease through the action of specialized, heat-producing adipocytes. Brown adipocytes are located in dedicated depots and express constitutively high levels of thermogenic genes, whereas inducible ‘brown-like’ adipocytes, also known as beige cells, develop in white fat in response to various activators. The activities of brown and beige fat cells reduce metabolic disease, including obesity, in mice and correlate with leanness in humans. Many genes and pathways that regulate brown and beige adipocyte biology have now been identified, providing a variety of promising therapeutic targets for metabolic disease.SUMMARY: The complexity of adipose tissue presents numerous challenges but also several opportunities for therapeutic intervention. There is persuasive evidence from animal models that enhancement of the function of brown adipocytes, beige adipocytes or both in humans could be very effective for treating type 2 diabetes and obesity. Moreover, there are now an extensive variety of factors and pathways that could potentially be targeted for therapeutic effects. In particular, the discoveries of circulating factors, such as irisin, fibroblast growth factor (FGF)21 and natriuretic peptides, that enhance brown and beige fat function in mice have garnered tremendous interest. Certainly, the next decade will see massive efforts to use beige and brown fat to ameliorate human metabolic disease.KEYWORDS: obesity, white adipose tissue, brown adipose tissue, beige adipose tissue, adipose organ, thermogenesis, energy expenditure

scholarly journals Knockdown of ANGPTL4 May Reduce the Expression of LPL during Differentiation of 3T3-L1 Preadipocyte

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Zhao X ◽  
◽  
Zhang F ◽  
Liu Y ◽  
Liu H ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Lipid Metabolism ◽  
Energy Homeostasis ◽  
Adipocyte Differentiation ◽  
Adipocyte Size ◽  
Preadipocyte Differentiation ◽  
Similar Expression Pattern ◽  
Genes Expression ◽  
Before And After ◽  
Ppar Signaling

Adipose tissue is a complex, highly metabolically active tissue. The expansion of adipose tissue is mainly affected by two processes: the number of adipocytes and the change of adipocyte size. Adipocyte differentiation is regulated by multiple factors. 3T3-L1 preadipocyte line has become the most widely studied cell line for adipocyte proliferation, differentiation and regulation of related genes. In our previous study, we found that ANGPTL4 was related to preadipocyte differentiation through PPAR signaling pathway. Recent studies have shown that ANGPTL4 has functions of regulating oncogenesis, vascular permeability, glucose homeostasis, lipid metabolism, energy homeostasis. In this study, we observed the changes of key genes expression before and after inhibiting ANGPTL4 to explore how ANGPTL4 influence on lipid metabolism. Results shows that, ANGPTL4 and LPL have similar expression pattern. We suspect that, ANGPTL4 and LPL may form a pathway, when ANGPTL4 is suppressed it may block the pathway and inhibit LPL.

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