While the link between obesity and type 2 diabetes is clear on an epidemiological level, the underlying mechanism linking these two common disorders is not as clearly understood. One hypothesis ...linking obesity to type 2 diabetes is the adipose tissue expandability hypothesis. The adipose tissue expandability hypothesis states that a failure in the capacity for adipose tissue expansion, rather than obesity
per se is the key factor linking positive energy balance and type 2 diabetes. All individuals possess a maximum capacity for adipose expansion which is determined by both genetic and environmental factors. Once the adipose tissue expansion limit is reached, adipose tissue ceases to store energy efficiently and lipids begin to accumulate in other tissues. Ectopic lipid accumulation in non-adipocyte cells causes lipotoxic insults including insulin resistance, apoptosis and inflammation. This article discusses the links between adipokines, inflammation, adipose tissue expandability and lipotoxicity. Finally, we will discuss how considering the concept of allostasis may enable a better understanding of how diabetes develops and allow the rational design of new anti diabetic treatments.
Extracellular vesicles (EVs) have emerged as a novel messaging system of the organism, mediating cell-cell and interorgan communication. Through their content of proteins and nucleic acids, as well ...as membrane proteins and lipid species, EVs can interact with and modulate the function of their target cells. The regulation of whole-body metabolism requires cross-talk between key metabolic tissues including adipose tissue (AT), the liver and skeletal muscle. Furthermore, the regulation of nutrient/energy allocation during pregnancy requires co-ordinated communication between the foetus and metabolic organs of the mother. A growing body of evidence is suggesting that EVs play a role in communication between and within key metabolic organs, both physiologically during metabolic homoeostasis but also contributing to pathophysiology during metabolic dysregulation observed in metabolic diseases such as obesity and diabetes. As obesity and its associated metabolic complications are reaching epidemic proportions, characterization of EV-mediated communication between key metabolic tissues may offer important insights into the regulation of metabolic functions during disease and offer global therapeutic opportunities. Here, we focus on the role of EVs in metabolic regulation and, in particular, EV-mediated cross-talk between cells of the AT.
Background and Aims
Hepatocytes undergo profound metabolic rewiring when primed to proliferate during compensatory regeneration and in hepatocellular carcinoma (HCC). However, the metabolic control ...of these processes is not fully understood. In order to capture the metabolic signature of proliferating hepatocytes, we applied state‐of‐the‐art systems biology approaches to models of liver regeneration, pharmacologically and genetically activated cell proliferation, and HCC.
Approach and Results
Integrating metabolomics, lipidomics, and transcriptomics, we link changes in the lipidome of proliferating hepatocytes to altered metabolic pathways including lipogenesis, fatty acid desaturation, and generation of phosphatidylcholine (PC). We confirm this altered lipid signature in human HCC and show a positive correlation of monounsaturated PC with hallmarks of cell proliferation and hepatic carcinogenesis.
Conclusions
Overall, we demonstrate that specific lipid metabolic pathways are coherently altered when hepatocytes switch to proliferation. These represent a source of targets for the development of therapeutic strategies and prognostic biomarkers of HCC.
If we could avoid the side effects associated with global sympathetic activation, activating brown adipose tissue to increase thermogenesis would be a safe way to lose weight. The discovery of ...adrenergic-independent brown fat activators opens the prospect of developing this alternative way to efficiently and safely induce negative energy balance.
This review focuses on adipose tissue biology and introduces the concept of adipose tissue plasticity and expandability as key determinants of obesity-associated metabolic dysregulation. This concept ...is fundamental to our understanding of adipose tissue as a dynamic organ at the center of nutritional adaptation. Here, we summarize the current knowledge of the mechanisms by which adipose tissue can affect peripheral energy homeostasis, particularly in the context of overnutrition. Two mechanisms emerge that provide a molecular understanding for obesity-associated insulin resistance. These are a) the dysregulation of adipose tissue expandability and b) the abnormal production of adipokines. This knowledge has the potential to pave the way for novel therapeutic concepts and strategies for managing and/or correcting complications associated with obesity and the metabolic syndrome.
Nonalcoholic fatty liver disease (NAFLD) can progress from simple steatosis (i.e., nonalcoholic fatty liver NAFL) to nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. Currently, the driver ...for this progression is not fully understood; in particular, it is not known how NAFLD and its early progression affects the distribution of lipids in the liver, producing lipotoxicity and inflammation. In this study, we used dietary and genetic mouse models of NAFL and NASH and translated the results to humans by correlating the spatial distribution of lipids in liver tissue with disease progression using advanced mass spectrometry imaging technology. We identified several lipids with distinct zonal distributions in control and NAFL samples and observed partial to complete loss of lipid zonation in NASH. In addition, we found increased hepatic expression of genes associated with remodeling the phospholipid membrane, release of arachidonic acid (AA) from the membrane, and production of eicosanoid species that promote inflammation and cell injury. The results of our immunohistochemistry analyses suggest that the zonal location of remodeling enzyme LPCAT2 plays a role in the change in spatial distribution for AA‐containing lipids. This results in a cycle of AA‐enrichment in pericentral hepatocytes, membrane release of AA, and generation of proinflammatory eicosanoids and may account for increased oxidative damage in pericentral regions in NASH. Conclusion: NAFLD is associated not only with lipid enrichment, but also with zonal changes of specific lipids and their associated metabolic pathways. This may play a role in the heterogeneous development of NAFLD. (Hepatology 2017;65:1165‐1180)
Adipose tissue and the liver play significant roles in the regulation of whole-body energy homeostasis, but they have not evolved to cope with the continuous, chronic, nutrient surplus seen in ...obesity. In this review, we detail how prolonged metabolic stress leads to adipose tissue dysfunction, inflammation, and adipokine release that results in increased lipid flux to the liver. Overall, the upshot of hepatic fat accumulation alongside an insulin-resistant state is that hepatic lipid enzymatic pathways are modulated and overwhelmed, resulting in the selective buildup of toxic lipid species, which worsens the pro-inflammatory and pro-fibrotic shift observed in nonalcoholic steatohepatitis.
The adipose tissue organ is organised as distinct anatomical depots located all along the body axis and it is constituted of three different types of adipocytes : white, beige and brown which are ...integrated with vascular, immune, neural and extracellular stroma cells. These distinct adipocytes serve different specialised functions. The main function of white adipocytes is to ensure healthy storage of excess nutrients/energy and its rapid mobilisation to supply the demand of energy imposed by physiological cues in other organs, whereas brown and beige adipocytes are designed for heat production through uncoupling lipid oxidation from energy production. The concert action of the three type of adipocytes/tissues has been reported to ensure an optimal metabolic status in rodents. However, when one or multiple of these adipose depots become dysfunctional as a consequence of sustained lipid/nutrient overload, then insulin resistance and associated metabolic complications ensue. These metabolic alterations negatively affects the adipose tissue functionality and compromises global metabolic homeostasis. Optimising white adipose tissue expandability and its functional metabolic flexibility and/or promoting brown/beige mediated thermogenic activity counteracts obesity and its associated lipotoxic metabolic effects. The development of these therapeutic approaches requires a deep understanding of adipose tissue in all broad aspects. In this chapter we will discuss the characteristics of the different adipose tissue depots with respect to origins and precursors recruitment, plasticity, cellular composition and expandability capacity as well as molecular and metabolic signatures in both physiological and pathophysiological conditions.
The adipose tissue expandability hypothesis suggests that the insulin resistance found in lipodystrophic and obese individuals is caused by the same pathogenic mechanism of impaired adipose tissue ...expansion capacity, even if the underlying cause and degree of impairment in adipose tissue expansion may be very different.\n It also integrates explanations of how changes in lipid handling and adipocyte size may interact to lead to inflammation, dyslipidaemia, and ultimately to diabetes. ...the adipose tissue expansion hypothesis may allow for the design of better obesity treatment regimes, particularly with respect to personalised weight loss programs.
Cell senescence is an important tumour suppressor mechanism and driver of ageing. Both functions are dependent on the development of the senescent phenotype, which involves an overproduction of ...pro‐inflammatory and pro‐oxidant signals. However, the exact mechanisms regulating these phenotypes remain poorly understood. Here, we show the critical role of mitochondria in cellular senescence. In multiple models of senescence, absence of mitochondria reduced a spectrum of senescence effectors and phenotypes while preserving ATP production via enhanced glycolysis. Global transcriptomic analysis by RNA sequencing revealed that a vast number of senescent‐associated changes are dependent on mitochondria, particularly the pro‐inflammatory phenotype. Mechanistically, we show that the ATM, Akt and mTORC1 phosphorylation cascade integrates signals from the DNA damage response (DDR) towards PGC‐1β‐dependent mitochondrial biogenesis, contributing to a ROS‐mediated activation of the DDR and cell cycle arrest. Finally, we demonstrate that the reduction in mitochondrial content in vivo, by either mTORC1 inhibition or PGC‐1β deletion, prevents senescence in the ageing mouse liver. Our results suggest that mitochondria are a candidate target for interventions to reduce the deleterious impact of senescence in ageing tissues.
Synopsis
Cellular senescence serves as an important anticancer growth arrest mechanism, but also contributes to ageing. This study shows that mitochondria are necessary for the pro‐inflammatory phenotype during senescence and that senescence can be induced by mitochondrial biogenesis.
Mitochondria are required for the development of the pro‐oxidant and pro‐inflammatory features of senescence.
ATM, Akt, mTOR and PGC‐1β‐mediated mitochondrial biogenesis are involved in a novel senescence signalling pathway.
Mitochondrial biogenesis stabilizes senescence via a positive feedback loop involving ROS and the DDR.
Cellular senescence serves as an important anticancer growth arrest mechanism, but also contributes to ageing. This study shows that mitochondria are necessary for the pro‐inflammatory phenotype during senescence and that senescence can be induced by mitochondrial biogenesis.
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