The prevalence of obesity is increasing and with it the prevalence of associated metabolic complications. Precisely how obesity results in metabolic disturbances remains unclear. In the face of ...persistent positive caloric balance, it has been postulated that the capacity of adipose tissue to safely store fat may be vital. This paper explores some of the evidence suggesting that the risk of developing metabolic disturbances is not related to how much fat an individual has, but how well their fat can expand to accommodate the caloric excess. If this is true, the metabolic consequences of obesity may arise from the inability to become more obese.
Diet is a major contributor to metabolic disease risk, but there is controversy as to whether increased incidences of diseases such as non-alcoholic fatty liver disease arise from consumption of ...saturated fats or free sugars. Here, we investigate whether a sub-set of triacylglycerols (TAGs) were associated with hepatic steatosis and whether they arise from de novo lipogenesis (DNL) from the consumption of carbohydrates.
We conduct direct infusion mass spectrometry of lipids in plasma to study the association between specific TAGs and hepatic steatosis assessed by ultrasound and fatty liver index in volunteers from the UK-based Fenland Study and evaluate clustering of TAGs in the National Survey of Health and Development UK cohort. We find that TAGs containing saturated and monounsaturated fatty acids with 16-18 carbons are specifically associated with hepatic steatosis. These TAGs are additionally associated with higher consumption of carbohydrate and saturated fat, hepatic steatosis, and variations in the gene for protein phosphatase 1, regulatory subunit 3b (PPP1R3B), which in part regulates glycogen synthesis. DNL is measured in hyperphagic ob/ob mice, mice on a western diet (high in fat and free sugar) and in healthy humans using stable isotope techniques following high carbohydrate meals, demonstrating the rate of DNL correlates with increased synthesis of this cluster of TAGs. Furthermore, these TAGs are increased in plasma from patients with biopsy-confirmed steatosis.
A subset of TAGs is associated with hepatic steatosis, even when correcting for common confounding factors. We suggest that hepatic steatosis risk in western populations is in part driven by increased DNL following carbohydrate rich meals in addition to the consumption of saturated fat.
Aims
Familial partial lipodystrophic syndrome 3 (FPLD3) is associated with mutations in the transcription factor PPARγ. One of these mutations, the P467L, confers a dominant negative effect. We and ...others have previously investigated the pathophysiology associated with this mutation using a humanized mouse model that recapitulates most of the clinical symptoms observed in patients who have been phenotyped under different experimental conditions. One of the key clinical manifestations observed, both in humans and mouse models, is the ectopic accumulation of fat in the liver. With this study we aim to dissect the molecular mechanisms that contribute to the excessive accumulation of lipids in the liver and characterize the negative effect of this PPARγ mutation on the activity of PPARα in vivo when activated by fibrates.
Material and Methods
P465L‐PPAR mutant and wild‐type mice were divided into 8 experimental groups, 4 different conditions per genotype. Briefly, mice were fed a chow diet or a high‐fat diet (HFD 45% Kcal from fat) for a period of 28 days and treated with WY14643 or vehicle for five days before culling. At the end of the experiment, tissues and plasma were collected. We performed extensive gene expression, fatty acid composition and histological analysis in the livers. The serum collected was used to measure several metabolites and to perform basic lipoprotein profile.
Results
P465L mice showed increased levels of insulin and free fatty acids (FFA) as well as increased liver steatosis. They also exhibit decreased levels of very low density lipoproteins (VLDL) when fed an HFD. We also provide evidence of impaired expression of a number of well‐established PPARα target genes in the P465L mutant livers.
Conclusion
Our data demonstrate that P465L confers partial resistance to the hypolipidemic action of fibrates. These results show that the fatty liver phenotype observed in P465L mutant mice is not only the consequence of dysfunctional adipose tissue, but also involves defective liver metabolism. All in all, the deleterious effects of P465L‐PPARγ mutation may be magnified by their collateral negative effect on PPARα function.
Scope
Consumption of products rich in flavan‐3‐ols, such as tea and cocoa, has been associated with decreased obesity, partially dependent on their capacity to enhance energy expenditure. Despite ...these phenolics having been reported to increase the thermogenic program in brown and white adipose tissue, flavan‐3‐ols are vastly metabolised in vivo to phenyl‐γ‐valerolactones. Therefore, we hypothesize that phenyl‐γ‐valerolactones may directly stimulate the differentiation and the activation of brown adipocytes.
Methods and results
Immortalized brown pre‐adipocytes were differentiated in presence of (R)‐5‐(3′,4′‐dihydroxyphenyl)‐γ‐valerolactone (VL1), (R)‐5‐(3´‐hydroxyphenyl)‐γ‐valerolactone‐4′‐O‐sulphate (VL2), (R)‐5‐phenyl‐γ‐valerolactone‐3´,4´‐di‐O‐sulphate (VL3), at concentrations of 2 or 10μM, whereas fully differentiated brown adipocyte were treated acutely (6‐24h). None of the treatments regulated the expression levels of the uncouple protein 1, nor of the main transcription factors involved in brown adipogenesis. Similarly, mitochondrial content was unchanged after treatments. Moreover these compounds did not display peroxisome proliferator‐activated receptor γ‐agonist activity, as evaluated by luciferase assay, and did not enhance norepinephrine‐stimulated lipolysis in mature adipocytes. However, both VL1 and VL2 prevented oxidative stress caused by H2O2.
Conclusion
Phenyl‐γ‐valerolactones and their sulphated forms do not influence brown adipocyte development or function at physiological or supraphysiological doses in vitro, but they are active protecting brown adipocytes from increased reactive oxygen species production.
Consumption of products rich in flavan‐3‐ols has been associated with increased energy expenditure. However, phenyl‐γ‐valerolactones (their major colonic metabolites) do not influence brown adipocyte differentiation or function in vitro. Accordingly, they do not modulate the expression of brown adipocytes markers. Moreover, they do not affect mitochondrial content or enhance norepinephrine‐stimulated lipolysis. Nevertheless, they can prevent an increase in reactive oxygen species.
Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either ...whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone-induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis.
White adipose tissue (WAT) mass is determined by adipocyte size and number. While adipocytes are continuously turned over, the mechanisms controlling fat cell number in WAT upon weight changes are ...unclear. Herein, prospective studies of human subcutaneous WAT demonstrate that weight gain increases both adipocyte size and number, but the latter remains unaltered after weight loss. Transcriptome analyses associate changes in adipocyte number with the expression of 79 genes. This gene set is enriched for growth factors, out of which one, transforming growth factor-β3 (TGFβ3), stimulates adipocyte progenitor proliferation, resulting in a higher number of cells undergoing differentiation in vitro. The relevance of these observations was corroborated in vivo where Tgfb3+/− mice, in comparison with wild-type littermates, display lower subcutaneous adipocyte progenitor proliferation, WAT hypertrophy, and glucose intolerance. TGFβ3 is therefore a regulator of subcutaneous adipocyte number and may link WAT morphology to glucose metabolism.
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•Increases in adipose mass lead to an irreversible increase in adipocyte number•Adipocyte number is linked to the adipose expression of a set of growth factors•Among these, only TGFβ3 stimulates adipocyte progenitor proliferation•Tgfb3+/− mice display adipose hypertrophy and glucose intolerance upon weight gain
The mechanisms regulating adipocyte number upon increases in white adipose tissue mass are not known. Here, by combining prospective clinical studies with cell and animal models, Petrus et al. report that transforming growth factor-β3 increases adipocyte precursor proliferation and thereby enables hyperplastic white adipose tissue expandability.
Human obesity-related diabetes and the accompanying metabolic disorders have been specifically linked to increased visceral adipose tissue mass. Understanding the differences in biology of the two ...human fat depots (visceral and subcutaneous) might hold the key to therapeutic strategies aimed at reducing obesity-induced insulin resistance and alleviating symptoms of the metabolic syndrome. Visfatin (pre-B-cell colony-enhancing factor, PBEF) is a novel adipokine that appears to be preferentially produced by visceral adipose tissue and has insulin-mimetic actions. Could this molecule hold the key to future treatments for type 1 and 2 diabetes? This article discusses the pros and cons of visfatin action and how it might affect future therapeutic strategies.
During cold exposure, activated brown adipose tissue (BAT) takes up a large amount of circulating glucose to fuel non-shivering thermogenesis and defend against hypothermia. However, little is known ...about the endocrine function of BAT controlling glucose homoeostasis under this thermoregulatory challenge. Here, we show that in male mice, activated BAT-derived extracellular vesicles (BDEVs) reprogram systemic glucose metabolism by promoting hepatic gluconeogenesis during cold stress. Cold exposure facilitates the selective packaging of miR-378a-3p-one of the BAT-enriched miRNAs-into EVs and delivery into the liver. BAT-derived miR-378a-3p enhances gluconeogenesis by targeting p110α. miR-378 KO mice display reduced hepatic gluconeogenesis during cold exposure, while restoration of miR-378a-3p in iBAT induces the expression of gluconeogenic genes in the liver. These findings provide a mechanistic understanding of BDEV-miRNA as stress-induced batokine to coordinate systemic glucose homoeostasis. This miR-378a-3p-mediated interorgan communication highlights a novel endocrine function of BAT in preventing hypoglycemia during cold stress.
RATIONALE:DNA damage is present in both genomic and mitochondrial DNA in atherosclerosis. However, whether DNA damage itself promotes atherosclerosis, or is simply a byproduct of the risk factors ...that promote atherosclerosis, is unknown.
OBJECTIVE:To examine the effect of DNA damage on atherosclerosis, we studied apolipoprotein (Apo)E mice that were haploinsufficient for the protein kinase ATM (ataxia telangiectasia mutated), which coordinates DNA repair.
METHODS AND RESULTS:ATM/ApoE mice developed accelerated atherosclerosis and multiple features of the metabolic syndrome, including hypertension, hypercholesterolemia, obesity, steatohepatitis, and glucose intolerance. Transplantation with ATM bone marrow attenuated atherosclerosis but not the metabolic syndrome. ATM smooth muscle cells and macrophages showed increased nuclear DNA damage and defective DNA repair signaling, growth arrest, and apoptosis. Metabolomic screening of ATM/ApoE mouse tissues identified metabolic changes compatible with mitochondrial defects, with increased β-hydroxybutyrate but reduced lactate, reduced glucose, and alterations in multiple lipid species. ATM/ApoE mouse tissues showed an increased frequency of a mouse mitochondrial “common” deletion equivalent and reduced mitochondrial oxidative phosphorylation.
CONCLUSIONS:We propose that failure of DNA repair generates defects in cell proliferation, apoptosis, and mitochondrial dysfunction. This in turn leads to ketosis, hyperlipidemia, and increased fat storage, promoting atherosclerosis and the metabolic syndrome. Prevention of mitochondrial dysfunction may represent a novel target in cardiovascular disease.
Regulation of body temperature critically depends on thyroid hormone (TH). Recent studies revealed that TH induces browning of white adipose tissue, possibly contributing to the observed hyperthermia ...in hyperthyroid patients and potentially providing metabolic benefits. Here, we show that browning by TH requires TH-receptor β and occurs independently of the sympathetic nervous system. The beige fat, however, lacks sufficient adrenergic stimulation and is not metabolically activated despite high levels of uncoupling protein 1 (UCP1). Studies at different environmental temperatures reveal that TH instead causes hyperthermia by actions in skeletal muscle combined with a central body temperature set-point elevation. Consequently, the metabolic and thermogenic effects of systemic hyperthyroidism were maintained in UCP1 knockout mice, demonstrating that neither beige nor brown fat contributes to the TH-induced hyperthermia and elevated glucose consumption, and underlining that the mere presence of UCP1 is insufficient to draw conclusions on the therapeutic potential of browning agents.
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