A systems biology analysis of lipolysis and fatty acid release from adipocytes in vitro and from adipose tissue in vivo

Lipolysis and the release of fatty acids to supply energy fuel to other organs, such as between meals, during exercise, and starvation, are fundamental functions of the adipose tissue. The intracellular lipolytic pathway in adipocytes is activated by adrenaline and noradrenaline, and inhibited by insulin. Circulating fatty acids are elevated in type 2 diabetic individuals. The mechanisms behind this elevation are not fully known, and to increase the knowledge a link between the systemic circulation and intracellular lipolysis is key. However, data on lipolysis and knowledge from in vitro systems have not been linked to corresponding in vivo data and knowledge in vivo. Here, we use mathematical modelling to provide such a link. We examine mechanisms of insulin action by combining in vivo and in vitro data into an integrated mathematical model that can explain all data. Furthermore, the model can describe independent data not used for training the model. We show the usefulness of the model by simulating new and more challenging experimental setups in silico, e.g. the extracellular concentration of fatty acids during an insulin clamp, and the difference in such simulations between individuals with and without type 2 diabetes. Our work provides a new platform for model-based analysis of adipose tissue lipolysis, under both non-diabetic and type 2 diabetic conditions.

A multi-level model analysis of lipolysis and fatty acid release from adipocytes in vitro and from adipose tissue in vivo

Lipolysis and the release of fatty acids to supply energy to other organs, such as between meals, during exercise, and starvation, are fundamental functions of the adipose tissue. The intracellular lipolytic pathway in adipocytes is activated by adrenaline and noradrenaline, and inhibited by insulin. Circulating fatty acids are elevated in type 2 diabetic individuals. The mechanisms behind this elevation are not fully known, and to increase the knowledge a link between the systemic circulation and intracellular lipolysis is key. However, data on lipolysis and knowledge from in vitro systems have not been linked to corresponding in vivo data and knowledge in vivo. Here, we use mathematical modelling to provide such a link. We examine mechanisms of insulin action by combining in vivo and in vitro data into an integrated mathematical model that can explain all data. Furthermore, the model can describe independent data not used for training the model. We show the usefulness of the model by simulating new and more challenging experimental setups in silico, e.g. the extracellular concentration of fatty acids during an insulin clamp, and the difference in such simulations between individuals with and without type 2 diabetes. Our work provides a new platform for model-based analysis of adipose tissue lipolysis, under both non-diabetic and type 2 diabetic conditions.

Antioxidants Effect of Two Aminomethyl Derivatives of 2-Methoxyphenol on Thermal and Storage Oxidative Stability of Coconut Oil

The antioxidants effect of two aminomethyl derivatives of 2-methoxyphenol: 4,6-di[(morpholin-4-yl)methyl]-2-methoxyphenol (DMMMP) and 5-[(pyrrolidin-1-yl)methyl]vanillic acid (PMVA) on enhancing thermal and oxidative storage stability of coconut oil was performed using tert-butylhydroxyquinone (TBHQ) as a comparative standard. The efficacy on thermal stability test was carried out by heating at 180 oC for 1, 3, and 6 hours, while the efficacy on the storage stability test was performed using an accelerated method by heating at 60oC for 5 weeks. The concentrations for MDMMP was 200, 350, and 500 ppm; for PMVA was 200, 275, and 350 ppm; and for TBHQ was 200 ppm. Free fatty acid (FFA) level, peroxide value (PV), and p-anisidine value (p-AV) were used as parameters to assess the level of oxidative stability of coconut oil. The results showed that the addition of DMMMP 200, 350, and 500 ppm, and PMVA 200 and 275 ppm did not inhibit FFA, peroxide, and aldehyde formation. In thermal stability study, PMVA (350 ppm) could inhibit the free fatty acid release, and formation of secondary oxidation products compounds on thermal stability comparable to TBHQ (200 ppm) addition, but only TBHQ that could inhibit peroxide formation for 6 h. In storage stability, DMMMP (all concentration) could not delay the fatty acid release, while PMVA (all concentration) and TBHQ (200 ppm) delayed that for 2 and 5 weeks, respectively. DMMMP (all concentration) delayed peroxide formation for 2 weeks, while PMVA (all concentration) and TBHQ (200 ppm) delayed peroxide formation for 5 weeks. All compounds only delay the formation of secondary oxidation products for 1 week. In conclusion, the efficacy of PMVA as an antioxidant against thermal and storage oxidative stability of coconut oil is higher than DMMMP but lower than TBHQ.

Assessment of Periprostatic and Subcutaneous Adipose Tissue Lipolysis and Adipocyte Size from Men with Localized Prostate Cancer

The prostate is surrounded by periprostatic adipose tissue (PPAT), the thickness of which has been associated with more aggressive prostate cancer (PCa). There are limited data regarding the functional characteristics of PPAT, how it compares to subcutaneous adipose tissue (SAT), and whether in a setting of localized PCa, these traits are altered by obesity or disease aggressiveness. PPAT and SAT were collected from 60 men (age: 42–78 years, BMI: 21.3–35.6 kg/m2) undergoing total prostatectomy for PCa. Compared to SAT, adipocytes in PPAT were smaller, had the same basal rates of fatty acid release (lipolysis) yet released less polyunsaturated fatty acid species, and were more sensitive to isoproterenol-stimulated lipolysis. Basal lipolysis of PPAT was increased in men diagnosed with less aggressive PCa (Gleason score (GS) ≤ 3 + 4) compared to men with more aggressive PCa (GS ≥ 4 + 3) but no other measured adipocyte parameters related to PCa aggressiveness. Likewise, there was no difference in PPAT lipid biology between lean and obese men. In conclusion, lipid biological features of PPAT do differ from SAT; however, we did not observe any meaningful difference in ex vivo PPAT biology that is associated with PCa aggressiveness or obesity. As such, our findings do not support a relationship between altered PCa behavior in obese men and the metabolic reprogramming of PPAT.

Insulin and β-adrenergic receptors mediate lipolytic and anti-lipolytic signalling that is not altered by type 2 diabetes in human adipocytes

Control of fatty acid storage and release in adipose tissue is fundamental in energy homeostasis and the development of obesity and type 2 diabetes. We here take the whole signalling network into account to identify how insulin and β-adrenergic stimulation in concert controls lipolysis in mature subcutaneous adipocytes obtained from non-diabetic and, in parallel, type 2 diabetic women. We report that, and show how, the anti-lipolytic effect of insulin can be fully explained by protein kinase B (PKB/Akt)-dependent activation of the phosphodiesterase PDE3B. Through the same PKB-dependent pathway β-adrenergic receptor signalling, via cAMP and PI3Kα, is anti-lipolytic and inhibits its own stimulation of lipolysis by 50%. Through this pathway both insulin and β-adrenergic signalling control phosphorylation of FOXO1. The dose–response of lipolysis is bell-shaped, such that insulin is anti-lipolytic at low concentrations, but at higher concentrations of insulin lipolysis was increasingly restored due to inhibition of PDE3B. The control of lipolysis was not altered in adipocytes from diabetic individuals. However, the release of fatty acids was increased by 50% in diabetes due to reduced reesterification of lipolytically liberated fatty acids. In conclusion, our results reveal mechanisms of control by insulin and β-adrenergic stimulation — in human adipocytes — that define a network of checks and balances ensuring robust control to secure uninterrupted supply of fatty acids without reaching concentrations that put cellular integrity at risk. Moreover, our results define how selective insulin resistance leave lipolytic control by insulin unaltered in diabetes, while the fatty acid release is substantially increased.

Why Craft Brewers Should Be Advised to Use Bottle Refermentation to Improve Late-Hopped Beer Stability

The aromatic complexity of craft beers, together with some particular practices (use of small vessels, dry hopping, etc.), can cause more oxidation associated with pre-maturated colloidal instability, Madeira off-flavors, bitterness decrease, and aroma loss. As bottle refermentation is widely used in Belgian craft beers, the aim of the present work is to assess how this practice might impact their flavor. In fresh beers, key flavors were evidenced by four complementary techniques: short-chain fatty acids determination, esters analysis, XAD-2 extract olfactometry, and overall sensory analysis. In almost all of the fresh beers, isovaleric acid was the sole fatty acid found above its sensory threshold. Selected samples were further analyzed through natural aging at 20 °C. The presence of yeast in the bottle minimized the trans-2-nonenal released from Schiff bases and proved less deleterious than suggested by previous studies with regard to fatty acid release and ester decrease through aging. Furthermore, according to the yeast species selected, some interesting terpenols and phenols were produced from glucosides during storage.

Free fatty acid release from vegetable and bovine milk fat-based infant formulas and human milk during two-phase in vitro digestion

The profile of fatty acids released during in vitro digestion of vegetable and bovine milk fat-based infant formula differ.