Secreted microRNAs (miRNAs) are novel endocrine factors that play essential pathological and physiological roles. Here, we report that pancreatic β cell‐released exosomal miR‐29 family members ...(miR‐29s) regulate hepatic insulin sensitivity and control glucose homeostasis. Cultured pancreatic islets were shown to secrete miR‐29s in response to high levels of free fatty acids (FFAs) in vitro. In vivo, high levels of FFAs, promoted by either high‐fat diet (HFD) feeding (physiopathological) or fasting (physiological), increased the secretion of miR‐29s into plasma. Intravenous administration of exosomal miR‐29s attenuated insulin sensitivity. The overexpression of miR‐29s in the β cells of transgenic (TG) mice promoted the secretion of miR‐29s and inhibited the insulin‐mediated suppression of glucose output in the liver. We used selective overexpression of traceable heterogenous mutant miR‐29s in β cells to confirm that islet‐derived exosomal miR‐29s target insulin signalling in the liver and blunt hepatic insulin sensitivity. Moreover, in vivo disruption of miR‐29s expression in β cells reversed HFD‐induced insulin resistance. In vitro experiments demonstrated that isolated exosomes enriched in miR‐29s inhibited insulin signalling in the liver and increased hepatic glucose production. These results unveil a novel β cell‐derived secretory signal—exosomal miR‐29s—and provide insight into the roles of miR‐29s in manipulating glucose homeostasis.
The mechanisms that drive nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This large multicenter study characterized the transcriptional changes that occur in liver tissue ...across the NAFLD spectrum as disease progresses to cirrhosis to identify potential circulating markers. We performed high-throughput RNA sequencing on a discovery cohort comprising histologically characterized NAFLD samples from 206 patients. Unsupervised clustering stratified NAFLD on the basis of disease activity and fibrosis stage with differences in age, aspartate aminotransferase (AST), type 2 diabetes mellitus, and carriage of
, a genetic variant associated with NAFLD. Relative to early disease, we consistently identified 25 differentially expressed genes as fibrosing steatohepatitis progressed through stages F2 to F4. This 25-gene signature was independently validated by logistic modeling in a separate replication cohort (
= 175), and an integrative analysis with publicly available single-cell RNA sequencing data elucidated the likely relative contribution of specific intrahepatic cell populations. Translating these findings to the protein level, SomaScan analysis in more than 300 NAFLD serum samples confirmed that circulating concentrations of proteins AKR1B10 and GDF15 were strongly associated with disease activity and fibrosis stage. Supporting the biological plausibility of these data, in vitro functional studies determined that endoplasmic reticulum stress up-regulated expression of
,
, and
, whereas GDF15 supplementation tempered the inflammatory response in macrophages upon lipid loading and lipopolysaccharide stimulation. This study provides insights into the pathophysiology of progressive fibrosing steatohepatitis, and proof of principle that transcriptomic changes represent potentially tractable and clinically relevant markers of disease progression.
White adipose tissue (WAT) has key metabolic and endocrine functions and plays a role in regulating energy homeostasis and insulin sensitivity. WAT is characterised by its capacity to adapt and ...expand in response to surplus energy through processes of adipocyte hypertrophy and/or recruitment and proliferation of precursor cells in combination with vascular and extracellular matrix remodelling. However, in the context of sustained obesity, WAT undergoes fibro-inflammation, which compromises its functionality, contributing to increased risk of type 2 diabetes and cardiovascular diseases. Conversely, brown adipose tissue (BAT) and browning of WAT represent potential therapeutic approaches, since dysfunctional white adipocyte-induced lipid overspill can be halted by BAT/browning-mediated oxidative anti-lipotoxic effects. Better understanding of the cellular and molecular pathophysiological mechanisms regulating adipocyte size, number and depot-dependent expansion has become a focus of interest over recent decades. Here, we summarise the mechanisms contributing to adipose tissue (AT) plasticity and function including characteristics and cellular complexity of the various adipose depots and we discuss recent insights into AT origins, identification of adipose precursors, pathophysiological regulation of adipogenesis and its relation to WAT/BAT expandability in obesity and its associated comorbidities.
Mitochondria are involved in a variety of cellular functions, including ATP production, amino acid and lipid biogenesis and breakdown, signalling and apoptosis. Mitochondrial dysfunction has been ...linked to neurodegenerative diseases, cancer and ageing. Although transcriptional mechanisms that regulate mitochondrial abundance are known, comparatively little is known about how mitochondrial function is regulated. Here we identify the metabolite stearic acid (C18:0) and human transferrin receptor 1 (TFR1; also known as TFRC) as mitochondrial regulators. We elucidate a signalling pathway whereby C18:0 stearoylates TFR1, thereby inhibiting its activation of JNK signalling. This leads to reduced ubiquitination of mitofusin via HUWE1, thereby promoting mitochondrial fusion and function. We find that animal cells are poised to respond to both increases and decreases in C18:0 levels, with increased C18:0 dietary intake boosting mitochondrial fusion in vivo. Intriguingly, dietary C18:0 supplementation can counteract the mitochondrial dysfunction caused by genetic defects such as loss of the Parkinson's disease genes Pink or Parkin in Drosophila. This work identifies the metabolite C18:0 as a signalling molecule regulating mitochondrial function in response to diet.
Tissue‐resident macrophages are required for homeostasis, but also contribute to tissue dysfunction in pathophysiological states. The sympathetic neurotransmitter norepinephrine (NE) induces an ...anti‐inflammatory and tissue‐reparative phenotype in macrophages. As NE has a well‐established role in promoting triglyceride lipolysis in adipocytes, and macrophages accumulate triglyceride droplets in various physiological and disease states, we investigated the effect of NE on primary mouse bone marrow‐derived macrophage triglyceride metabolism. Surprisingly, our data show that in contrast to the canonical role of NE in stimulating lipolysis, NE acting via beta2‐adrenergic receptors (B2ARs) in macrophages promotes extracellular fatty acid uptake and their storage as triglycerides and reduces free fatty acid release from triglyceride‐laden macrophages. We demonstrate that these responses are mediated by a B2AR activation‐dependent increase in Hilpda and Dgat1 gene expression and activity. We further show that B2AR activation favors the storage of extracellular polyunsaturated fatty acids. Finally, we present evidence that macrophages isolated from hearts after myocardial injury, for which survival critically depends on leukocyte B2ARs, have a transcriptional signature indicative of a transient triglyceride accumulation. Overall, we describe a novel and unexpected role of NE in promoting triglyceride storage in macrophages that could have potential implications in multiple diseases.
The different shades of fat Peirce, Vivian; Carobbio, Stefania; Vidal-Puig, Antonio
Nature (London),
06/2014, Letnik:
510, Številka:
7503
Journal Article
Recenzirano
Our understanding of adipose tissue biology has progressed rapidly since the turn of the century. White adipose tissue has emerged as a key determinant of healthy metabolism and metabolic ...dysfunction. This realization is paralleled only by the confirmation that adult humans have heat-dissipating brown adipose tissue, an important contributor to energy balance and a possible therapeutic target for the treatment of metabolic disease. We propose that the development of successful strategies to target brown and white adipose tissues will depend on investigations that elucidate their developmental origins and cell-type-specific functional regulators.
Aging, obesity, and insulin resistance are associated with low levels of PGC1α and PGC1β coactivators and defective mitochondrial function. We studied mice deficient for PGC1α and PGC1β double ...heterozygous (DH) to investigate their combined pathogenic contribution. Contrary to our hypothesis, DH mice were leaner, had increased energy dissipation, a pro‐thermogenic profile in BAT and WAT, and improved carbohydrate metabolism compared to wild types. WAT showed upregulation of mitochondriogenesis/oxphos machinery upon allelic compensation of PGC1α4 from the remaining allele. However, DH mice had decreased mitochondrial OXPHOS and biogenesis transcriptomes in mitochondria‐rich organs. Despite being metabolically healthy, mitochondrial defects in DH mice impaired muscle fiber remodeling and caused qualitative changes in the hepatic lipidome. Our data evidence first the existence of organ‐specific compensatory allostatic mechanisms are robust enough to drive an unexpected phenotype. Second, optimization of adipose tissue bioenergetics is sufficient to maintain a healthy metabolic phenotype despite a broad severe mitochondrial dysfunction in other relevant metabolic organs. Third, the decrease in PGC1s in adipose tissue of obese and diabetic patients is in contrast with the robustness of the compensatory upregulation in the adipose of the DH mice.
Inflammation and lipid accumulation are hallmarks of muscular pathologies resulting from metabolic diseases such as obesity and type 2 diabetes. During obesity, the hypertrophy of visceral adipose ...tissue (VAT) contributes to muscle dysfunction, particularly through the dysregulated production of adipokines. We have investigated the cross talk between human adipocytes and skeletal muscle cells to identify mechanisms linking adiposity and muscular dysfunctions. First, we demonstrated that the secretome of obese adipocytes decreased the expression of contractile proteins in myotubes, consequently inducing atrophy. Using a three-dimensional coculture of human myotubes and VAT adipocytes, we showed the decreased expression of genes corresponding to skeletal muscle contractility complex and myogenesis. We demonstrated an increased secretion by cocultured cells of cytokines and chemokines with interleukin (IL)-6 and IL-1β as key contributors. Moreover, we gathered evidence showing that obese subcutaneous adipocytes were less potent than VAT adipocytes in inducing these myotube dysfunctions. Interestingly, the atrophy induced by visceral adipocytes was corrected by IGF-II/insulin growth factor binding protein-5. Finally, we observed that the skeletal muscle of obese mice displayed decreased expression of muscular markers in correlation with VAT hypertrophy and abnormal distribution of the muscle fiber size. In summary, we show the negative impact of obese adipocytes on muscle phenotype, which could contribute to muscle wasting associated with metabolic disorders.
Brown and beige fat: From molecules to physiology and pathophysiology Carobbio, Stefania; Guénantin, Anne-Claire; Samuelson, Isabella ...
Biochimica et biophysica acta. Molecular and cell biology of lipids,
January 2019, 2019-01-00, 20190101, Letnik:
1864, Številka:
1
Journal Article
Recenzirano
The adipose organ portrays adipocytes of diverse tones: white, brown and beige, each type with distinct functions. Adipocytes orchestrate their adaptation and expansion to provide storage to excess ...nutrients, the quick mobilisation of fuel to supply peripheral functional demands, insulation, and, in their thermogenic form, heat generation to maintain core body temperature. Thermogenic adipocytes could be targets for anti-obesity and anti-diabetic therapeutic approaches aiming to restore adipose tissue functionality and increase energy dissipation. However, for thermogenic adipose tissue to become therapeutically relevant, a better understanding of its development and origins, its progenitors and their characteristics and the composition of its niche, is essential. Also crucial is the identification of stimuli and molecules promoting its specific differentiation and activation. Here we highlight the structural/cellular differences between human and rodent brown adipose tissue and discuss how obesity and metabolic complication affects brown and beige cells as well as how they could be targeted to improve their activation and improve global metabolic homeostasis. Finally, we describe the limitations of current research models and the advantages of new emerging approaches.
•Obesity is defined as pathological excessive expansion of adipose tissue.•Brown and beige fat cells main function is to dissipate energy.•Thermogenic adipocytes are promising anti-obesity targets.•Multiple endocrine factors regulate thermogenic adipocyte activation.•Human PSCs represent new tools to study adipocyte physiology and pathophysiology.
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