Adipose Tissue Fibrosis in Obesity: Etiology and Challenges

2021 ◽  
Vol 84 (1) ◽  
Author(s):  
Geneviève Marcelin ◽  
Emmanuel L. Gautier ◽  
Karine Clément
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Molecular Mechanisms ◽  
Whole Body ◽  
Annual Review ◽  
Publication Date ◽  
Tissue Fibrosis ◽  
Adipose Tissue Remodeling ◽  
Metabolic Dysfunctions ◽  
Body Energy

Obesity is a chronic and progressive process affecting whole-body energy balance and is associated with comorbidities development. In addition to increased fat mass, obesity induces white adipose tissue (WAT) inflammation and fibrosis, leading to local and systemic metabolic dysfunctions, such as insulin resistance (IR). Accordingly, limiting inflammation or fibrosis deposition may improve IR and glucose homeostasis. Although no targeted therapy yet exists to slow or reverse adipose tissue fibrosis, a number of findings have clarified the underlying cellular and molecular mechanisms. In this review, we highlight adipose tissue remodeling events shown to be associated with fibrosis deposition, with a focus on adipose progenitors involved in obesity-induced healthy as well as unhealthy WAT expansion. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Mechanism by which arylamine N-acetyltransferase 1 ablation causes insulin resistance in mice

2017 ◽  
Vol 114 (52) ◽  
pp. E11285-E11292 ◽  
Author(s):  
João Paulo Camporez ◽  
Yongliang Wang ◽  
Kasper Faarkrog ◽  
Natsasi Chukijrungroat ◽  
Kitt Falk Petersen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Molecular Mechanisms ◽  
Whole Body ◽  
Mitochondrial Activity ◽  
Single Nucleotide ◽  
Brown Adipose ◽  
Nat2 Gene ◽  
Body Energy

A single-nucleotide polymorphism in the human arylamine N-acetyltransferase 2 (Nat2) gene has recently been identified as associated with insulin resistance in humans. To understand the cellular and molecular mechanisms by which alterations in Nat2 activity might cause insulin resistance, we examined murine ortholog Nat1 knockout (KO) mice. Nat1 KO mice manifested whole-body insulin resistance, which could be attributed to reduced muscle, liver, and adipose tissue insulin sensitivity. Hepatic and muscle insulin resistance were associated with marked increases in both liver and muscle triglyceride (TAG) and diacylglycerol (DAG) content, which was associated with increased PKCε activation in liver and increased PKCθ activation in skeletal muscle. Nat1 KO mice also displayed reduced whole-body energy expenditure and reduced mitochondrial oxygen consumption in white adipose tissue, brown adipose tissue, and hepatocytes. Taken together, these studies demonstrate that Nat1 deletion promotes reduced mitochondrial activity and is associated with ectopic lipid-induced insulin resistance. These results provide a potential genetic link among mitochondrial dysfunction with increased ectopic lipid deposition, insulin resistance, and type 2 diabetes.

Inflammation and impaired adipogenesis in hypertrophic obesity in man

2009 ◽  
Vol 297 (5) ◽  
pp. E999-E1003 ◽  
Author(s):  
Birgit Gustafson ◽  
Silvia Gogg ◽  
Shahram Hedjazifar ◽  
Lachmi Jenndahl ◽  
Ann Hammarstedt ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Subcutaneous Adipose Tissue ◽  
Molecular Mechanisms ◽  
Whole Body ◽  
Preadipocyte Differentiation ◽  
Metabolic Complications ◽  
Adipose Cell ◽  
Subcutaneous Adipose ◽  
Adipose Cell Size

Obesity is associated mainly with adipose cell enlargement in adult man (hypertrophic obesity), whereas the formation of new fat cells (hyperplastic obesity) predominates in the prepubertal age. Adipose cell size, independent of body mass index, is negatively correlated with whole body insulin sensitivity. Here, we review recent findings linking hypertrophic obesity with inflammation and a dysregulated adipose tissue, including local cellular insulin resistance with reduced IRS-1 and GLUT4 protein content. In addition, the number of preadipocytes in the abdominal subcutaneous adipose tissue capable of undergoing differentiation to adipose cells is reduced in hypertrophic obesity. This is likely to promote ectopic lipid accumulation, a well-known finding in these individuals and one that promotes insulin resistance and cardiometabolic risk. We also review recent results showing that TNFα, but not MCP-1, resistin, or IL-6, completely prevents normal adipogenesis in preadipocytes, activates Wnt signaling, and induces a macrophage-like phenotype in the preadipocytes. In fact, activated preadipocytes, rather than macrophages, may completely account for the increased release of chemokines and cytokines by the adipose tissue in obesity. Understanding the molecular mechanisms for the impaired preadipocyte differentiation in the subcutaneous adipose tissue in hypertrophic obesity is a priority since it may lead to new ways of treating obesity and its associated metabolic complications.

scholarly journals Cellular insulin resistance disrupts hypothalamic mHypoA-POMC/GFP neuronal signaling pathways

2013 ◽  
Vol 220 (1) ◽  
pp. 13-24 ◽  
Author(s):  
Anaies Nazarians-Armavil ◽  
Jennifer A Chalmers ◽  
Claire B Lee ◽  
Wenqing Ye ◽  
Denise D Belsham
Keyword(s):  
Insulin Resistance ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Second Messengers ◽  
Mrna Level ◽  
Neuronal Cell ◽  
Whole Body ◽  
Cell Models ◽  
Metabolic Hormones ◽  
Body Energy

POMC neurons play a central role in the maintenance of whole-body energy homeostasis. This balance requires proper regulation of POMC neurons by metabolic hormones, such as insulin. However, the heterogeneous cellular population of the intact hypothalamus presents challenges for examining the molecular mechanisms underlying the potent anorexigenic effects of POMC neurons, and there is currently a complete lack of mature POMC neuronal cell models for study. To this end, we have generated novel, immortalized, adult-derived POMC-expressing/α-MSH-secreting cell models, mHypoA-POMC/GFP lines 1–4, representing the fluorescence-activated cell-sorted POMC population from primary POMC-eGFP mouse hypothalamus. The presence of Pomc mRNA in these cell lines was confirmed, and α-MSH was detected via immunofluorescence. α-MSH secretion in the mHypoA-POMC/GFP-1 was found to increase in response to 10 ng/ml ciliary neurotrophic factor (CNTF) or 10 nM insulin as determined by enzyme immunoassay. Further experiments using the mHypoA-POMC/GFP-1 cell line revealed that 10 ng/ml CNTF increases Pomc mRNA at 1 and 2 h after treatment, whereas insulin elicited an increase in Pomc mRNA level and decreases in insulin receptor (Insr (Ir)) mRNA level at 4 h. Furthermore, the activation of IR-mediated downstream second messengers was examined by western blot analysis, following the induction of cellular insulin resistance, which resulted in a loss of insulin-mediated regulation of Pomc and Ir mRNAs. The development of these immortalized neurons will be invaluable for the elucidation of the cellular and molecular mechanisms that underlie POMC neuronal function under normal and perturbed physiological conditions.

Omega-3 Fatty Acids and Adipose Tissue: Inflammation and Browning

2020 ◽  
Vol 40 (1) ◽  
pp. 25-49 ◽  
Author(s):  
Nishan Sudheera Kalupahana ◽  
Bimba Lakmini Goonapienuwala ◽  
Naima Moustaid-Moussa
Keyword(s):  
Fatty Acids ◽  
Weight Loss ◽  
Adipose Tissue ◽  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Whole Body ◽  
Omega 3 ◽  
Brown Adipose ◽  
Body Energy

White adipose tissue (WAT) and brown adipose tissue (BAT) are involved in whole-body energy homeostasis and metabolic regulation. Changes to mass and function of these tissues impact glucose homeostasis and whole-body energy balance during development of obesity, weight loss, and subsequent weight regain. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), which have known hypotriglyceridemic and cardioprotective effects, can also impact WAT and BAT function. In rodent models, these fatty acids alleviate obesity-associated WAT inflammation, improve energy metabolism, and increase thermogenic markers in BAT. Emerging evidence suggests that ω-3 PUFAs can also modulate gut microbiota impacting WAT function and adiposity. This review discusses molecular mechanisms, implications of these findings, translation to humans, and future work, especially with reference to the potential of these fatty acids in weight loss maintenance.

scholarly journals Glycemic index differences of high-fat diets modulate primarily lipid metabolism in murine adipose tissue

2011 ◽  
Vol 43 (15) ◽  
pp. 942-949 ◽  
Author(s):  
Evert M. van Schothorst ◽  
Annelies Bunschoten ◽  
Eline Verlinde ◽  
Patrick Schrauwen ◽  
Jaap Keijer
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glycemic Index ◽  
Molecular Mechanisms ◽  
Serum Levels ◽  
Whole Body ◽  
High Fat ◽  
Beneficial Effects ◽  
Ppar Γ

A low vs. high glycemic index of a high-fat (HF) diet (LGI and HGI, respectively) significantly retarded adverse health effects in adult male C57BL/6J mice, as shown recently (Van Schothorst EM, Bunschoten A, Schrauwen P, Mensink RP, Keijer J. FASEB J 23: 1092–1101, 2009). The LGI diet enhanced whole body insulin sensitivity and repressed HF diet-induced body and white adipose tissue (WAT) weight gain, resulting in significantly reduced serum leptin and resistin levels and increased adiponectin levels. We questioned how WAT is modulated and characterized the molecular mechanisms underlying the glycemic index-mediated effects using whole genome microarrays. This showed that the LGI diet mainly exerts its beneficial effects via substrate metabolism, especially fatty acid metabolism. In addition, cell adhesion and cytoskeleton remodeling showed reduced expression, in line with lower WAT mass. An important transcription factor showing enhanced expression is PPAR-γ. Furthermore, serum levels of triglycerides, total cholesterol, and HDL- and LDL-cholesterol were all significantly reduced by LGI diet, and simultaneously muscle insulin sensitivity was significantly increased as analyzed by protein kinase B/Akt phosphorylation. Cumulatively, even though these mice were fed an HF diet, the LGI diet induced significantly favorable changes in metabolism in WAT. These effects suggest a partial overlap with pharmacological approaches by thiazolidinediones to treat insulin resistance and statins for hypercholesterolemia. It is therefore tempting to speculate that such a dietary approach might beneficially support pharmacological treatment of insulin resistance or hypercholesterolemia in humans.

scholarly journals Adipogenic progenitors in different organs: Pathophysiological implications

2021 ◽  
Author(s):  
Francesca Favaretto ◽  
Silvia Bettini ◽  
Luca Busetto ◽  
Gabriella Milan ◽  
Roberto Vettor
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Adipogenic Differentiation ◽  
Whole Body ◽  
Low Grade ◽  
Functional Changes ◽  
Age Related ◽  
Mesenchymal Precursor Cells ◽  
Adipose Tissue Remodeling ◽  
Adipose Organ

AbstractIn physiological conditions, the adipose organ resides in well-defined areas, where it acts providing an energy supply and as an endocrine organ involved in the control of whole-body energy metabolism. Adipose tissue adipokines connect the body’s nutritional status to the regulation of energy balance. When it surrounds organs, it provides also for mechanical protection. Adipose tissue has a complex and heterogenous cellular composition that includes adipocytes, adipose tissue-derived stromal and stem cells (ASCs) which are mesenchymal stromal cells, and endothelial and immune cells, which signal to each other and to other tissues to maintain homeostasis. In obesity and in other nutrition related diseases, as well as in age-related diseases, biological and functional changes of adipose tissue give rise to several complications. Obesity triggers alterations of ASCs, impairing adipose tissue remodeling and adipose tissue function, which induces low-grade systemic inflammation, progressive insulin resistance and other metabolic disorders. Adipose tissue grows by hyperplasia recruiting new ASCs and by hypertrophy, up to its expandability limit. To overcome this limitation and to store the excess of nutrients, adipose tissue develops ectopically, involving organs such as muscle, bone marrow and the heart. The origin of ectopic adipose organ is not clearly elucidated, and a possible explanation lies in the stimulation of the adipogenic differentiation of mesenchymal precursor cells which normally differentiate toward a lineage specific for the organ in which they reside. The chronic exposition of these newly-formed adipose depots to the pathological environment, will confer to them all the phenotypic characteristics of a dysfunctional adipose tissue, perpetuating the organ alterations. Visceral fat, but also ectopic fat, either in the liver, muscle or heart, can increase the risk of developing insulin resistance, type 2 diabetes, and cardiovascular diseases. Being able to prevent and to target dysfunctional adipose tissue will avoid the progression towards the complications of obesity and other nutrition-related diseases. The aim of this review is to summarize some of the knowledge regarding the presence of adipose tissue in particular tissues (where it is not usually present), describing the composition of its adipogenic precursors, and the interactions responsible for the development of organ pathologies.

scholarly journals Liver mitochondria and insulin resistance.

2010 ◽  
Vol 57 (4) ◽  
Author(s):  
Guillaume Vial ◽  
Hervé Dubouchaud ◽  
Xavier M Leverve
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Energy Homeostasis ◽  
Cell Types ◽  
Short Review ◽  
Liver Mitochondria ◽  
Whole Body ◽  
Public Health Issue ◽  
Metabolic Dysfunctions ◽  
Body Energy

With a steadily increasing prevalence, insulin resistance (IR) is a major public health issue. This syndrome is defined as a set of metabolic dysfunctions associated with, or contributing to, a range of serious health problems. These disorders include type 2 diabetes, metabolic syndrome, obesity, and non-alcoholic steatohepatitis (NASH). According to the literature in the field, several cell types like β-cell, myocyte, hepatocyte and/or adipocyte, as well as related complex signaling environment involved in peripheral insulin sensitivity are believed to be central in this pathology. Because of the central role of the liver in the whole-body energy homeostasis, liver insulin sensitivity and its potential relationship with mitochondrial oxidative phosphorylation appear to be crucial. The following short review highlights how liver mitochondria could be implicated in IR and should therefore be considered as a specific therapeutic target in the future.

scholarly journals The Role of AMPK Signaling in Brown Adipose Tissue Activation

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1122
Author(s):  
Jamie I. van der van der Vaart ◽  
Mariëtte R. Boon ◽  
Riekelt H. Houtkooper
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Whole Body ◽  
Ampk Signaling ◽  
Mitochondrial Homeostasis ◽  
Brown Adipose ◽  
Metabolic Stresses ◽  
Amp Activated Protein Kinase ◽  
Body Energy

Obesity is becoming a pandemic, and its prevalence is still increasing. Considering that obesity increases the risk of developing cardiometabolic diseases, research efforts are focusing on new ways to combat obesity. Brown adipose tissue (BAT) has emerged as a possible target to achieve this for its functional role in energy expenditure by means of increasing thermogenesis. An important metabolic sensor and regulator of whole-body energy balance is AMP-activated protein kinase (AMPK), and its role in energy metabolism is evident. This review highlights the mechanisms of BAT activation and investigates how AMPK can be used as a target for BAT activation. We review compounds and other factors that are able to activate AMPK and further discuss the therapeutic use of AMPK in BAT activation. Extensive research shows that AMPK can be activated by a number of different kinases, such as LKB1, CaMKK, but also small molecules, hormones, and metabolic stresses. AMPK is able to activate BAT by inducing adipogenesis, maintaining mitochondrial homeostasis and inducing browning in white adipose tissue. We conclude that, despite encouraging results, many uncertainties should be clarified before AMPK can be posed as a target for anti-obesity treatment via BAT activation.

KCTD10 regulates brown adipose tissue thermogenesis and metabolic function via Notch Signaling

2021 ◽  
Author(s):  
Mingsheng Ye ◽  
Liping Luo ◽  
Qi Guo ◽  
Guanghua Lei ◽  
Chao Zeng ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Notch Signaling ◽  
Molecular Mechanisms ◽  
Uncoupling Protein ◽  
Notch Signaling Pathway ◽  
Whole Body ◽  
Brown Adipocyte ◽  
Metabolic Function ◽  
Brown Adipose

Brown adipose tissue (BAT) is emerging as a target to beat obesity through the dissipation of chemical energy to heat. However, the molecular mechanisms of brown adipocyte thermogenesis remain to be further elucidated. Here, we show that KCTD10, a member of the polymerase delta-interacting protein 1 (PDIP1) family, was reduced in BAT by cold stress and a β3 adrenoceptor agonist. Moreover, KCTD10 level increased in the BAT of obese mice, and KCTD10 overexpression attenuates uncoupling protein 1 (UCP1) expression in primary brown adipocytes. BAT-specific KCTD10 knockdown mice had increased thermogenesis and cold tolerance protecting from high fat diet (HFD)-induced obesity. Conversely, overexpression of KCTD10 in BAT caused reduced thermogenesis, cold intolerance, and obesity. Mechanistically, inhibiting Notch signaling restored the KCTD10 overexpression suppressed thermogenesis. Our study presents that KCTD10 serves as an upstream regulator of notch signaling pathway to regulate BAT thermogenesis and whole-body metabolic function.

Sign in / Sign up

Export Citation Format

Share Document