Fasta skapar inflammation i fettvävnaden

[King Grub]

Objective

The human adaptive fasting response enables survival during periods of caloric deprivation. A crucial component of the fasting response is the shift from glucose metabolism to utilization of lipids, underscoring the importance of adipose tissue as the central lipid-storing organ. The objective of this study was to investigate the response of adipose tissue to a prolonged fast in humans.

Methods

We performed RNA sequencing of subcutaneous adipose tissue samples longitudinally collected during a 10-day, 0-calorie fast in humans. We further investigated observed transcriptional signatures utilizing cultured human monocytes and Thp1 cells. We examined the cellularity of adipose tissue biopsies with transmission electron microscopy and tested for associated changes in relevant inflammatory mediators in the systemic circulation by ELISA assays of longitudinally collected blood samples.

Results

Coincident with the expected shift away from glucose utilization and lipid storage, we demonstrated downregulation of pathways related to glycolysis, oxidative phosphorylation, and lipogenesis. The canonical lipolysis pathway was also downregulated, whereas fasting drove alternative lysosomal paths to lipid digestion. Unexpectedly, the dominant induced pathways were associated with immunity and inflammation, although this only became evident at the 10-day time point. Among the most augmented transcripts were those associated with macrophage identity and function, such as members of the erythroblast transformation-specific (ETS) transcription factor family. Key components of the macrophage transcriptional signal in fasting adipose tissue were recapitulated with induced expression of two of the ETS transcription factors via cultured macrophages, SPIC and SPI1. The inflammatory signal was further reflected by an increase in systemic inflammatory mediators.

Conclusions

Collectively, this study demonstrates an unexpected role of metabolic inflammation in the human adaptive fasting response.

Molecular Metabolism, 28 September 2020, Prolonged fasting drives a program of metabolic inflammation in human adipose tissue.

https://www.sciencedirect.com/scienc...12877820301563

[Bifftek]

Är det något bra eller dåligt?

[Masterpan]

Ursprungligen postat av Bifftek

Är det något bra eller dåligt?

Svårt att veta med enbart denna information. Långt pågående inflammation i kroppen är dåligt dock.

[Pepz]

Ursprungligen postat av Bifftek

Är det något bra eller dåligt?

.

klistrar in diskussionen från studien här

4. Discussion
In this study, serial transcriptomics of subcutaneous AT over a 10-day fast demonstrated an unexpected dominant signal of inflammation, including augmentation of transcripts related to macrophage identity and function. Orthogonal analyses demonstrating macrophage influx in AT biopsy specimens and a corollary surge in systemically circulating inflammatory markers further established an inflammatory response to prolonged fasting.

Prior cross-sectional studies of the AT transcriptome revealed associations between inflammatory pathways and obesity or clinical metrics of insulin resistance and diabetes [16]. Prospective longitudinal studies have demonstrated transcriptional attenuation of such inflammatory pathways in AT with weight loss achieved over weeks to months [[17], [18], [19]]. In murine AT, fasting leads to an acute reduction in macrophages found in close association with blood vessels [20]. In contrast, our observation of increased AT inflammation with fasting is perhaps most consistent with the augmentation of macrophage numbers observed in the AT of obese mice subjected to caloric restriction [21]. An important difference between our study and many prior human AT transcriptional analyses is that our study population was (1) normal to overweight and not obese and (2) relatively young and healthy without known metabolic disease. It is possible that the effects of fasting are quite different in the AT of obese/diabetic individuals with baseline inflammation. Differences in timing may also be important. When reconciling murine-human differences, for example, it may be that the mechanisms underpinning the mobilization of AT lipid concurrent with 10–15% weight loss in just 24 h are different than what is a slower process in humans who lose approximately 9.2% over 10 days [11]. In addition, while we did not have interval transcriptional data between the day 1 and day 10 time points, circulating inflammatory markers appear to peak between days 3 and 5 before trending downward. By day 10, we also observed an increase in local transcription and circulating levels of the anti-inflammatory cytokine IL-10. Whether this suggestion of an ongoing programmatic shift to immunomodulatory activity would continue in a sustained fashion weeks after refeeding is an important question for future study.

There also may be important differences between more subtle degrees of negative caloric balance and the response to a zero-calorie fast in which the shift to lipid metabolism and ketogenesis is imperative. One potential role for inflammatory cells, and particularly macrophages, in AT is to scavenge and metabolize lipids or lipid byproducts. When adipocytes undergo cell death, for example, macrophages surround and phagocytose the remnants including the lipid droplet(s) [22]. In mice, contraction of AT mass over several weeks of caloric restriction drives a macrophage population that supports lipolysis [21]. Recent data also support a role for macrophages in homeostatic lipid turnover in AT [10]. Therefore, we speculate that macrophages may also play a functional role in lipid catabolism during fasting; however, the analyses conducted in this study cannot exclude alternative mechanisms such as the elucidation of inflammatory pathways as a non-specific stress response to prolonged fasting.

Our observation of an AT inflammatory response to fasting is notable given the transcriptional downregulation of genes encoding the canonical lipases thought to effect lipolysis during fasting in adipocytes inclusive of MGLL, PNPLA2, and LIPE. Delayed transcriptional induction of LIPE with fasting was previously demonstrated and considered to represent a possible disconnect between gene transcription and the level and/or activity of the enzyme [23]. While our study certainly cannot exclude such a disconnect, our data point to the possibility of additional lysosomal-dependent mechanisms of lipolysis as also being operative during fasting. One challenge in interpreting the lysosomal signal, however, is that it was observed in analyses of unfractionated AT and therefore the signal could indicate lipophagic activity by either adipocytes or inflammatory cells. A unifying explanation to the dual signals of an inflammatory surge and lysosomal lipolysis pathways is that both arise from macrophages and that macrophages directly contribute to the mobilization and catabolic digestion of triglycerides. For this to be true, there would have to be a mechanism for transport of triglycerides from adipocyte lipid droplets to interstitial macrophages, as only fatty acids, not intact triglycerides, can freely diffuse through plasma membranes. Importantly, a recent study identified a new lipase-independent mechanism of adipocyte lipid droplet remodeling in which undigested triglycerides are directly released from adipocytes within extracellular vesicles [10]. We speculate that this process could be operative as a complementary mechanism for mobilizing stored lipids during fasting.

Our study also identified the transcription factor SPIC as a candidate marker and mediator of a fasting metabolic phenotype in AT macrophages. Ex vivo, the expression of SPIC was augmented in monocytes exposed to a fatty acid stimulus and SPIC gain of function drove a transcriptional signature that overlapped with that observed in AT with fasting, providing conceptual support for SPIC as a mediator of macrophage specification in AT. This potential role of SPIC deviates from murine studies in which SPIC lineage tracing and myeloid loss of function demonstrate a role of SPIC as a master regulator of red pulp macrophage specification in the spleen [13,14]. Our data may indicate a broader repertoire of SPIC functions or alternatively reflect interspecies differences in the transcriptional mechanisms of macrophage specification. An additional question is the underlying degree of macrophage heterogeneity and whether AT macrophages converge on a common phenotype with fasting. While each induced transcription factor (for example, SPIC and SPI1) could control distinct macrophage phenotypes, it is perhaps more likely that they represent a circuit of collaborating transcription factors that are increasingly recognized to establish specialized cell states [24,25]. However, our study cannot definitively answer this question, in part due to the challenge of deciphering the relative degrees to which transcriptional changes in AT arise from transcriptional reprogramming vs changes in cellularity. In the future, some of these questions may be addressed by applying single-cell sequencing methods to human AT with fasting, as has recently been performed in calorically restricted rats [26].

In recent years, there has been increasing interest in the use of fasting protocols to improve metabolic health and longevity [27]. One proposed mechanism of benefit from fasting has been modulation of inflammation and specifically that fasting may induce anti-inflammatory pathways. Our data suggest that the effects of fasting on the immune/inflammatory system may be more complex as the transcriptional and systemic signals elicited by fasting in our study cannot be easily categorized as pro- or anti-inflammatory. Whether the reprogramming of AT with fasting would be beneficial if sustained cannot be addressed by this study. However, it is possible that the mechanisms that have evolved to enable humans to undertake the metabolic shifts required to survive starvation may include both beneficial and harmful factors. It is also possible that the net benefit of pathways activated by fasting are context dependent. For example, the psychiatric disorder anorexia nervosa, which is characterized by a state of self-induced chronic caloric restriction and low body weight, is associated with maladaptive pathology such as significant bone fragility and is among the psychiatric diseases with the highest mortality rate [1,28]. In contrast, individuals who are overweight or obese may incur additional metabolic benefits from fasting due to decreased adiposity. Therefore, an important open question, underscored but not answered by our study, is whether fasting in humans induces beneficial pathways that promote longevity independent of effects on adiposity. Nonetheless, our study provides a direct link between fasting physiology and reprogramming of metabolic inflammation in AT, the underlying mechanisms of which may hold one key to understanding the beneficial effects of fasting in humans.

[skyffelmördarn]

Ursprungligen postat av Masterpan

Svårt att veta med enbart denna information. Långt pågående inflammation i kroppen är dåligt dock.

Men om det är i fettvävnaden kanske det inte är lika farligt?

[samsam]

Ursprungligen postat av Bifftek

Är det något bra eller dåligt?

Check: Detta var efter 10 dagars fasta.
Förmodligen lite överstyr för att bara ge positiva effekter.

[TotteShaped4Life]

Inflammation i fettet ett nödvändigt ont
[PRESSMEDDELANDE, 2010-03-25] Man har länge antagit att inflammation i fettvävnaden är en bidragande orsak till nedsatt funktion av hormonet insulin - så kallad insulinresistens - och i förlängningen vuxendiabetes, diabetes typ 2. Men i en artikel i topprankade New England Journal of Medicine ifrågasätter nu en forskargrupp vid Karolinska Institutet teorin att fettinflammation enbart är av ondo. De publicerade resultaten talar istället för att en viss typ av inflammation är nödvändig för den normala fettvävnadens nybildning och nedbrytning av fettceller.
https://nyheter.ki.se/inflammation-i...nodvandigt-ont

[TotteShaped4Life]

- Det här styrker hypotesen att det finns ett samband mellan den lokala inflammationen i fettvävnad och den inflammationsprocess som är central i utvecklingen av ateroskleros och som kan leda till hjärtkärlsjukdom. Vi hoppas också kunna utvärdera om markörer för inflammerat fett är relaterat till sådan utveckling. Om inflammation i fettväv kan ha stor betydelse för både insulinresistens och hjärtkärlsjukdomar är det viktigt att förstå hur man kan påverka detta. Till exempel om en ökad fysisk aktivitet kan minska inflammationen. Man har observerat förändringar i fettväv vid en ganska måttlig ökning av motion, men kanske, säger Rachel Fisher, krävs det lite mer fysisk aktivitet för att man ska kunna se tydligare förändringar i inflammerat fett.

- Det är fortfarande mycket vi inte förstår när det gäller hur fettväven fungerar och vilka konsekvenser det ger. En ökad kunskap bakom de processer som stimulerar inflammation i fettväv ökar möjligheterna att i framtiden kunna kontrollera denna process och därmed förbättra prognosen för personer med risk för hjärtkärlsjukdomar.https://ki.se/forskning/rubbningar-i...r-hela-kroppen