Storage Capacity Of Adipose Tissue Research Articles

Pathogenesis of MASLD and MASH - role of insulin resistance and lipotoxicity.

Insulin resistance and lipotoxicity are extremely interconnected but fundamental in setting the stage for the development of MASLD/MASH. A comprehensive literature search was performed and key themes were synthesised to provide insight into the underlying molecular mechanisms of insulin resistance and lipotoxicity in the liver, muscle, pancreas and adipose tissue and how organ cross-talk is fundamental to driving disease pathogenesis. Classical thinking postulates that excess FFA load exceeds the storage capacity of adipose tissue, which is predicated upon both genetic and environmental factors. This results in insulin resistance and compensatory hyperinsulinaemia by pancreatic beta cells to overcome target organ insulin resistance. As adipocyte dysfunction worsens, not only are excess FFA delivered to other organs, including skeletal muscle, pancreas and liver but a pro-inflammatory milieu is established with increases in IL-6, TNF-α and changes in adipokine levels (increased leptin and decreased adiponectin). With increased intramuscular lipid accumulation, lipotoxic species decrease insulin signalling, reduce glucose uptake by downregulation of GLUT4 and decrease glycogen synthesis. With this additional reduced capacity, hyperglycaemia is further exacerbated and increased FFA are delivered to the liver. The liver has the largest capacity to oxidise fat and to adapt to these stressors and, therefore, has become the last line of defence for excess lipid storage and utilisation, the capacity of which may be impacted by genetic and environmental factors. However, when the liver can no longer keep up with increasing FFA delivery and DNL, lipotoxic species accumulate with ensuing mitochondrial dysfunction, increased ER stress, oxidant stress and inflammasome activation, all of which drive hepatocyte injury and apoptosis. The resulting wound healing response, marked by stellate cell activation, drives collagen accumulation, progressive fibrosis, and, ultimately, end organ failure and death. This vicious cycle and complex interplay between insulin resistance, hyperinsulinaemia, lipotoxicity and multi-directional cross-talk among different target organs are critical drivers of MASLD/MASH. Targeting tissue-specific insulin resistance and hyperinsulinaemia while decreasing FFA load (lipotoxicity) through dietary and lifestyle changes remain the best upstream interventions.

Suppressive Effect of Fraxetin on Adipogenesis and Reactive Oxygen Species Production in 3T3-L1 Cells by Regulating MAPK Signaling Pathways

Recent studies have identified obesity as one of the world’s most serious chronic disorders. Adipogenesis, in which preadipocytes are differentiated into mature adipocytes, has a decisive role in establishing the number of adipocytes and determining the lipid storage capacity of adipose tissue and fat mass in adults. Fat accumulation in obesity is implicated with elevated oxidative stress in adipocytes induced by reactive oxygen species (ROS). Adipogenesis regulation by inhibiting adipogenic differentiation and ROS production has been selected as the strategy to treat obesity. The conventional anti-obesity drugs allowed by the U.S. Food and Drug Administration have severe adverse effects. Therefore, various natural products have been developed as a solution for obesity, suppressing adipogenic differentiation. Fraxetin is a major component extracted from the stem barks of Fraxinus rhynchophylla, with various bioactivities, including anti-inflammatory, anticancer, antioxidant, and antibacterial functions. However, the effect of fraxetin on adipogenesis is still not clearly understood. We studied the pharmacological functions of fraxetin in suppressing lipid accumulation and its underlying molecular mechanisms involving 3T3-L1 preadipocytes. Moreover, increased ROS production induced by a mixture of insulin, dexamethasone, and 3-isobutylmethylxanthine (MDI) in 3T3-L1 was attenuated by fraxetin during adipogenesis. These effects were regulated by mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, our findings imply that fraxetin possesses inhibitory roles in adipogenesis and can be a potential anti-obesity drug.

Adipose tissue: from amorphous filler to metabolic mastermind

Adipose tissue plays a central role in the control of systemic glucose homeostasis through two major mechanisms: fat storage and secretion of specific cytokines known as adipokines. Fat storage in adipose tissue is critically important, as it prevents lipid deposition in liver and muscle, which in turn results in insulin resistance and increased risk of type 2 diabetes. Secretion of adipokines, such as leptin, protects from fuel depletion through appetite control, and other adipokines control fuel distribution and utilization. Fat storage capacity of adipose tissue increases through two mechanisms, adipocyte hypertrophy and adipocyte hyperplasia. Adipose tissue depots expand differently in diverse individuals and confer varying degrees of metabolic disease risk. There are multiple adipocyte subtypes that together mediate the functions of adipose tissue. They do so through specialized functions such as thermogenesis, which burns fuel to maintain core temperature, and through selective secretion of different adipokines. Much progress has been made in understanding the mechanisms by which adipose tissue controls systemic metabolism, increasing our hope of developing new, effective therapies for metabolic diseases.

RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro

Fat distribution is an independent cardiometabolic risk factor. However, its molecular and cellular underpinnings remain obscure. Here we demonstrate that two independent GWAS signals at RSPO3, which are associated with increased body mass index-adjusted waist-to-hip ratio, act to specifically increase RSPO3 expression in subcutaneous adipocytes. These variants are also associated with reduced lower-body fat, enlarged gluteal adipocytes and insulin resistance. Based on human cellular studies RSPO3 may limit gluteofemoral adipose tissue (AT) expansion by suppressing adipogenesis and increasing gluteal adipocyte susceptibility to apoptosis. RSPO3 may also promote upper-body fat distribution by stimulating abdominal adipose progenitor (AP) proliferation. The distinct biological responses elicited by RSPO3 in abdominal versus gluteal APs in vitro are associated with differential changes in WNT signalling. Zebrafish carrying a nonsense rspo3 mutation display altered fat distribution. Our study identifies RSPO3 as an important determinant of peripheral AT storage capacity.

Evidence of genetic predisposition for metabolically healthy obesity and metabolically obese normal weight.

Obesity has evolved into a global pandemic that constitutes a major threat to public health. The majority of obesity-related health care costs are due to cardiometabolic complications, such as insulin resistance, dyslipidemia, and hypertension, which are risk factors for Type 2 diabetes and cardiovascular disease. However, many obese individuals, often called metabolically healthy obese (MHO), seem to be protected from these cardiometabolic complications. Conversely, there is a group of individuals who suffer from cardiometabolic complications despite being of normal weight; a condition termed metabolically obese normal weight (MONW). Recent large-scale genomic studies have provided evidence that a number of genetic variants show an association with increased adiposity but a favorable cardiometabolic profile, an indicator for the genetic basis of the MHO and MONW phenotypes. Many of these loci are located in or near genes that implicate pathways involved in adipogenesis, fat distribution, insulin signaling, and insulin resistance. It has been suggested that a threshold for subcutaneous adipose tissue expandability may be at play in the manifestation of MHO and MONW, where expiry of adipose tissue storage capacity could lead to ectopic lipid accumulation in non-adipose tissues such as liver, muscle, heart, and pancreatic beta cells. Understanding the genetic aspects of the mechanisms that underpin MHO and MONW is crucial to define appropriate public health action points and to develop effective intervention measures.

Chemotherapy diminishes lipid storage capacity of adipose tissue in a preclinical model of colon cancer

BackgroundAccelerated loss of adipose tissue in cancer is associated with shorter survival, and reduced quality of life. Evidence is emerging suggesting tumour association with alterations in adipose tissue, but much less is known about drug-related mechanisms contributing to adipose atrophy. Identification of mechanisms by which tumour and cancer treatments, such as chemotherapy, affect adipose tissue are required to develop appropriate therapeutic interventions to prevent fat depletion in cancer. This pre-clinical study aimed to assess alterations in adipose tissue during the clinical course of cancer.MethodsFischer 344 rats bearing the Ward colorectal tumour were euthanized before chemotherapy, after 1- cycle, or 2-cycles of a combination chemotherapy consisting of Irinotecan (CPT-11) combined with 5-fluorouracil (5-FU), which recapitulates first line treatment for human colorectal cancer. Periuterine adipose tissue was isolated. Healthy rats served as a reference group. Histological analysis (hematoxylin and eosin), Real-time PCR (TaqMan) and proteomic analysis (LC-MS/MS) were performed.ResultsLarger adipocytes (3993.7 ± 52.6 μm2) in tumour-bearing animals compared to the reference group (3227.7 ± 36.7 μm2; p < 0.001) was associated with reduced expression of proteins involved in mitochondrial fatty acid oxidation. The presence of a tumour has a significant effect on phospholipid but not triglyceride fatty acid composition. There were greater proportions of saturated fatty acids concurrent with lower monounsaturated fatty acids within the PL fraction of adipocytes in tumour-bearing animals. Chemotherapy treatment decreased the size of adipocytes (2243.9 ± 30.4 μm2; p < 0.001) and led to depletion of n-3 polyunsaturated fatty acids in adipose tissue triglyceride. Evaluation of the proteome profile revealed decreased expression of proteins involved in ATP generation, β-oxidation, and lipogenesis. Overall, adipose tissue may not be able to efficiently oxidize fatty acids to provide energy to maintain energy demanding pathways like lipogenesis inside the tissue.ConclusionsIn conclusion, metabolic adaptations to mitochondrial impairment may contribute to diminished lipid storage capacity of adipose tissue following chemotherapy delivery.

GLP-1 analogue-induced weight loss does not improve obesity-induced AT dysfunction.

Glucagon-like peptide-1 (GLP-1) analogues aid weight loss that improves obesity-associated adipose tissue (AT) dysfunction. GLP-1 treatment may however also directly influence AT that expresses the GLP-1 receptor (GLP-1R). The present study aimed to assess the impact of GLP-1 analogue treatment on subcutaneous AT (SCAT) inflammatory and fibrotic responses, compared with weight loss by calorie reduction (control). Among the 39 participants with Type2 diabetes recruited, 30 age-matched participants were randomized to 4 months treatment with Liraglutide (n=22) or calorie restriction based on dietetic counselling (n=8). Assessments included clinical characteristics and repeated subcutaneous abdominal AT biopsies. Liraglutide resulted in weight loss in most participants (-3.12±1.72kg, P=0.007) and significant reduction in visceral AT (VAT). It was more effective in lowering fasting glucose, in comparison with weight loss by dieting. However, tumour necrosis factor-α (TNFA) AT-expression (P=0.0005), macrophage chemoattractant protein-1 (MCP-1) expression (P=0.027) and its serum levels (P=0.048) increased with Liraglutide, suggestive of an inflammatory response unlike in the diet arm in which a trend of lower cluster of differentiation 14 (CD14) expression (P=0.09) was found. Liraglutide treatment also increased expression of factors involved in extracellular matrix (ECM) deposition, transforming growth factor-β (TGFB) and collagen type 1 alpha 1 chain (COL1A1) (TGFB1: before 0.73±0.09 arbitrary units (AU), after 1.00±0.13 AU, P=0.006; COL1A1: 0.84±0.09 AU compared with 1.49±0.26 AU, P=0.026). Liraglutide thus appears to induce an inflammatory response in AT and influences ECM remodelling. Despite its superior effect on glycaemia, Liraglutide does not improve obesity-associated AT dysfunction in subcutaneous tissue. It is yet unclear whether this limits AT storage capacity for lipids. This may be of importance in patients being re-exposed to positive energy balance such as post GLP-1 discontinuation.

The sparing use of fat: G0s2 controls lipolysis and fatty acid oxidation.

switch protein 2HFD High-fat dietWAT White adipose tissueTriacylglycerols represent the largest energy reservoir of thebody. The primary fat storage organ is white adipose tissue(WAT), which grows in response to excess energy intake,eventually leading to obesity, and shrinks in response tostarvation. In addition to its function as an energy storageorgan, the finely tuned regulation of triacylglycerol synthesisand degradation in WAT is required for control of circulatinglipid levels. Defective WAT function may result indyslipidaemia and fatty acid overload of non-adipose tissues,inducingectopictriacylglycerol deposition,whichisassociat-ed with insulin resistance, inflammation and impaired meta-bolic function of insulin-sensitive tissues [1]. This can occurin obese individuals when the storage capacity of adiposetissue is exceeded and in patients with loss-of-function muta-tions in genes regulating lipid storage, e.g. mutations in thegene encoding lipid droplet protein perilipin 1, which limitstheaccessoflipasestofatstores,leadingtolipodystrophyandsevere insulin resistance [2]. Thus, efficient fatty acid storagein the form of inert triacylglycerol can be considered as aprotective mechanism counteracting dyslipidaemia and meta-bolic disease.In the current issue of Diabetologia, El-Assaad et al [3]describe the phenotype of mice lacking G0s2, the proteinproduct of which (G

Influence of Upper and Lower Body Adipose Tissue on Insulin Sensitivity in South Asian Men

BackgroundSouth Asians have a high prevalence of insulin resistance, which predisposes to type 2 diabetes.RationaleIn the current study, we examined whether insulin sensitivity in South Asian men and men of...

TNFα gene knockout differentially affects lipid deposition in liver and skeletal muscle of high-fat-diet mice

Aims/hypothesisInflammation and ectopic lipid deposition contribute to obesity-related insulin resistance (IR). Studies have shown that deficiency of the proinflammatory cytokine tumor necrosis factor-α (TNFα) protects against the IR induced by a high-fat diet (HFD). We aimed to evaluate the relationship between HFD-related inflammation and lipid deposition in skeletal muscle and liver. Experimental designWild-type (WT) and TNFα-deficient (TNFα-KO) mice were subjected to an HFD for 12 weeks. A glucose tolerance test was performed to evaluate IR. Inflammatory status was assessed by measuring plasma and tissue transcript levels of cytokines. Lipid intermediate concentrations were measured in plasma, muscle and liver. The expression of genes involved in fatty acid transport, synthesis and oxidation was analyzed in adipose tissue, muscle and liver. ResultsHFD induced a higher body weight gain in TNFα-KO mice than in WT mice. The weight of epididymal and abdominal adipose tissues was twofold lower in WT mice than in TNFα-KO mice, whereas liver weight was significantly heavier in WT mice. IR, systemic and adipose tissue inflammation, and plasma nonesterified fatty acid levels were reduced in TNFα-KO mice fed an HFD. TNFα deficiency improved fatty acid metabolism and had a protective effect against lipid deposition, inflammation and fibrosis associated with HFD in liver but had no impact on these markers in muscle. ConclusionsOur data suggest that in an HFD context, TNFα deficiency reduced hepatic lipid accumulation through two mechanisms: an increase in adipose tissue storage capacity and a decrease in fatty acid uptake and synthesis in the liver.

De Novo Lipogenesis in Adipose Tissue Is Associated with Course of Morbid Obesity after Bariatric Surgery

Objective De novo lipogenesis is involved in fatty acid biosynthesis and could be involved in the regulation of the triglyceride storage capacity of adipose tissue. However, the association between lipogenic and lipolytic genes and the evolution of morbidly obese subjects after bariatric surgery remains unknown. In this prospective study we analyze the association between the improvement in the morbidly obese patients as a result of bariatric surgery and the basal expression of lipogenic and lipolytic genes.MethodsWe study 23 non diabetic morbidly obese patients who were studied before and 7 months after bariatric surgery. Also, we analyze the relative basal mRNA expression levels of lipogenic and lipolytic genes in epiploic visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT).ResultsWhen the basal acetyl-CoA carboxylase 1 (ACC1), acetyl-CoA synthetase 2 (ACSS2) and ATP citrate lyase (ACL) expression in SAT was below percentile-50, there was a greater decrease in weight (P = 0.006, P = 0.034, P = 0.026), body mass index (P = 0.008, P = 0.033, P = 0.034) and hip circumference (P = 0.033, P = 0.021, P = 0.083) after bariatric surgery. In VAT, when the basal ACSS2 expression was below percentile-50, there was a greater decrease in hip circumference (P = 0.006). After adjusting for confounding variables in logistic regression models, only the morbidly obese patients with SAT or VAT ACSS2 expression≥P50 before bariatric surgery had a lower percentage hip circumference loss (<P50) after bariatric surgery (SAT: P = 0.039; VAT: P = 0.033).ConclusionsA lower basal ACSS2, ACC1 and ACL expression, genes involved in de novo lipogenesis, is associated with a better evolution of anthropometric variables after bariatric surgery. Thus, the previous state of the pathways involved in fatty acid metabolism may have repercussions on the improvement of these patients.

Obesity and Insulin Resistance-Related Changes in the Expression of Lipogenic and Lipolytic Genes in Morbidly Obese Subjects

The storage capacity of adipose tissue may be an important factor linking obesity, insulin resistance (IR), and associated morbidities. The aim of this study was to analyze the expression of lipogenic and lipolytic genes in adipose tissue and the influence of IR. We studied the mRNA expression of peroxisome proliferator-activated receptor-γ (PPARγ) and lipogenic and lipolytic enzymes in the visceral (VAT) and subcutaneous adipose tissue (SAT) from 23 morbidly obese patients (MO; 13 with low IR and ten with high IR) and from 15 healthy, lean controls. In the VAT and SAT from the MO, we found an increased expression of PPARγ (p = 0.001 and p = 0.022, respectively), acyl-coenzyme A (CoA)/cholesterol acyltransferase (p < 0.001 and p < 0.001), aquaporin 7 (p < 0.001 and p = 0.003), and adipose triglyceride lipase (p < 0.001 and p < 0.001) and a reduced expression of acetyl-coenzyme A carboxylase (p = 0.004 and p < 0.001), independently of the state of IR. The expression of phosphoenolpyruvate carboxykinase and acyl-CoA synthetase, however, was significantly lower in the MO with high IR (p < 0.05). Glycerol kinase (p = 0.010), hormone-sensitive lipase (p < 0.001), and perilipin (p = 0.006) were only significantly increased in VAT. Acyl-CoA synthetase (p = 0.012) and fatty acid binding protein-4 (p = 0.003) were only significantly decreased in SAT. The expression of the genes studied was only greater in the SAT than the VAT in the controls. Our results show an upregulation of genes facilitating triglyceride/fatty acid cycling and a reduction in the genes involved in de novo synthesis of fatty acids in morbid obesity. The expression of some of the genes studied seems to be related with the state of IR. VAT and SAT differ metabolically and also between controls and MO.

Diabetes and apoptosis: lipotoxicity

Obesity is an established risk factor in the pathogenesis of insulin resistance, type 2 diabetes mellitus and cardiovascular disease; all components that are part of the metabolic syndrome. Traditionally, insulin resistance has been defined in a glucocentric perspective. However, elevated systemic levels of fatty acids are now considered significant contributors towards the pathophysiological aspects associated with the syndrome. An overaccumulation of unoxidized long-chain fatty acids can saturate the storage capacity of adipose tissue, resulting in a lipid 'spill over' to non-adipose tissues, such as the liver, muscle, heart, and pancreatic-islets. Under these circumstances, such ectopic lipid deposition can have deleterious effects. The excess lipids are driven into alternative non-oxidative pathways, which result in the formation of reactive lipid moieties that promote metabolically relevant cellular dysfunction (lipotoxicity) and programmed cell-death (lipoapoptosis). Here, we focus on how both of these processes affect metabolically significant cell-types and highlight how lipotoxicity and sequential lipoapoptosis are as major mediators of insulin resistance, diabetes and cardiovascular disease.

The role of the renin-angiotensin-aldosterone system in diabetes and its vascular complications

Clinical trials have demonstrated the benefit of blood pressure (BP) reduction in reducing the risk of cardiovascular and renal complications in patients with diabetes mellitus. Incorporation of agents that inhibit the renin-angiotensin-aldosterone system (RAAS) into antihypertensive regimens has been shown to provide reductions in renal and cardiovascular events that are mediated by both BP-dependent and -independent mechanisms. Recent studies exploring these potential mechanisms have demonstrated a direct role of angiotensin II (ATII) in the pathology of the vasculature and other sites of end-organ injury. In animal models of diabetes, inhibition of the RAAS with angiotensin-converting enzyme (ACE) inhibition or angiotensin type 1 (AT(1)) receptor blockade has been shown to prevent atherosclerosis, an effect that was independent of BP reduction. In addition to its direct effects on the vasculature, ATII also has direct detrimental effects on end organs, including the kidney and the heart, which lead to the development of proteinuria and left ventricular hypertrophy (LVH), respectively. Left ventricular hypertrophy has been shown to be predictive of cardiovascular and renal events, and the benefits of RAAS inhibition with angiotensin receptor blocker therapy are accompanied by a reduction in LVH. In addition to preventing the cardiovascular and renal complications of diabetes, the RAAS blockade has also been shown, in several large randomized clinical trials, to inhibit new onset of diabetes. Recent studies have revealed that many tissues, including pancreatic islets and adipose tissue, have a local RAAS. In the diabetic rat model (Zucker diabetic fatty rats), pancreatic islets exhibit an increased intraislet expression of ACE and AT(1) as well as increased intraislet fibrosis, apoptosis, and oxidative stress. The local RAAS also appears to play a role in the function of the adipocyte. Angiotensin II inhibits adipocyte differentiation, potentially decreasing the storage capacity of adipose tissue. The reduced capacity of adipose tissue to store fatty acids may cause their accumulation in other tissues, leading to insulin resistance and development of diabetes. Collectively, these studies demonstrate that ATII has direct effects on multiple tissues, and inhibition of ATII action in these tissues may be responsible for many of the clinical benefits observed with RAAS inhibition.

Expansion of adipose tissue storage capacity at different ages in rats

The expansion of adipose tissue storage capacity with growth and with dietary, fat-induced obesity was studied in Sprague-Dawley and Osborne-Mendel rats by a combination of techniques. Mature adipocytes were counted and measured morphometrically. All heavy cells were counted after collagenase liberation, and then subjected to different culture procedures. An aliquot part was cultured in a suspension medium which prevented cellular multiplication, and was asssumed to allow an estimation of in vivo determined, non-filled precursor cells to adipocytes (preadipocytes) by their filling with lipid in this system. Simple purification steps allowed another aliquot of the heavy cells to multiply and form, essentially quantitatively, adipocytes or preadipocytes in a confluent monolayer in a substrate-rich culture-medium. Before confluence these cells are not determined to cells in the adipocyte series and were therefore called adipoblasts. Their rate of multiplication was determined by measurement of rate of incorporation of labelled thymidine into DNA. The results obtained are compatible with the following integrated picture. Adipose tissue of the young rat is growing by an increased multiplication of adipoblasts, which after determination to preadipocytes fill up to adipocytes until the tissue is full-grown. Cells other than adipocytes continue to increase in number with age. In the adult rat fat-feeding results in expansion of adipose depots, first by increase in fat cell size. Formation of adipoblasts and cells for supply and support of adipocytes is triggered early. This “readiness” of the precursor pool of cells, not yet recruited to adipocytes, is a generalized phenomenon. When the increased demand for triglyceride storage can no longer be met by an expansion of available adipocytes, which now have reached a “critical size” and are “full”, then cells from the adipoblast precursor pool are recruited and are determined to become preadipocytes, which are rapidly filled with triglycerides to mature adipocytes. This determination is presumably triggered by a local signal and is associated with the degree of cellular expansion. Sprague-Dawley rats are less sensitive to fat-feeding than Osborne-Mendel rats and showed only part of this development.