Agné Kulyté

Bio: Agné Kulyté is an academic researcher from Karolinska Institutet. The author has contributed to research in topics: Adipose tissue & Adipocyte. The author has an hindex of 18, co-authored 42 publications receiving 1490 citations. Previous affiliations of Agné Kulyté include Linköping University & Karolinska University Hospital.

MicroRNA regulatory networks in human adipose tissue and obesity

Abstract: MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression and, therefore, biological processes in different tissues. A major function of miRNAs in adipose tissue is to stimulate or inhibit the differentiation of adipocytes, and to regulate specific metabolic and endocrine functions. Numerous miRNAs are present in human adipose tissue; however, the expression of only a few is altered in individuals with obesity and type 2 diabetes mellitus or are differentially expressed in various adipose depots. In humans, obesity is associated with chronic low-grade inflammation that is regulated by signal transduction networks, in which miRNAs, either directly or indirectly (through regulatory elements such as transcription factors), influence the expression and secretion of inflammatory proteins. In addition to their diverse effects on signalling, miRNAs and transcription factors can interact to amplify the inflammatory effect. Although additional miRNA signal networks in human adipose tissue are not yet known, similar regulatory circuits have been described in brown adipose tissue in mice. miRNAs can also be secreted from fat cells into the circulation and serve as markers of disturbed adipose tissue function. Given their role in regulating transcriptional networks, miRNAs in adipose tissue might offer tangible targets for treating metabolic disorders.

Adipose Tissue MicroRNAs as Regulators of CCL2 Production in Human Obesity

Abstract: In obesity, white adipose tissue (WAT) inflammation is linked to insulin resistance. Increased adipocyte chemokine (C-C motif) ligand 2 (CCL2) secretion may initiate adipose inflammation by attracting the migration of inflammatory cells into the tissue. Using an unbiased approach, we identified adipose microRNAs (miRNAs) that are dysregulated in human obesity and assessed their possible role in controlling CCL2 production. In subcutaneous WAT obtained from 56 subjects, 11 miRNAs were present in all subjects and downregulated in obesity. Of these, 10 affected adipocyte CCL2 secretion in vitro and for 2 miRNAs (miR-126 and miR-193b), regulatory circuits were defined. While miR-126 bound directly to the 3′-untranslated region of CCL2 mRNA, miR-193b regulated CCL2 production indirectly through a network of transcription factors, many of which have been identified in other inflammatory conditions. In addition, overexpression of miR-193b and miR-126 in a human monocyte/macrophage cell line attenuated CCL2 production. The levels of the two miRNAs in subcutaneous WAT were significantly associated with CCL2 secretion (miR-193b) and expression of integrin, α-X, an inflammatory macrophage marker (miR-193b and miR-126). Taken together, our data suggest that miRNAs may be important regulators of adipose inflammation through their effects on CCL2 release from human adipocytes and macrophages.

Regulation of lipolysis in small and large fat cells of the same subject.

Abstract: Context: Large fat cell size is linked to type 2 diabetes risk and may involve an enhanced rate of adipocyte lipolysis causing elevated levels of fatty acids. Objective: Our objective was to study the role of fat cell size in the regulation of lipolysis within a subject. Design and Main Outcome Measures: Subcutaneous adipose tissue was obtained from 16 healthy subjects. Large and small adipocytes were isolated for each sample. Hormonal regulation of lipolysis and expression of lipolysis-regulating proteins were investigated. Results: No effect of cell size on the rate of lipolysis was observed when lipolysis was expressed per lipid weight of fat cells. However, when expressed per number of fat cells, the lipolysis was significantly higher in large as compared with small adipocytes. This was observed in both the unstimulated (basal) state and in the presence of the major lipolysis-regulating hormones such as catecholamines (stimulating), natriuretic peptides (stimulating), and insulin (inhibiting). The rec...

Adipose tissue pathways involved in weight loss of cancer cachexia

Abstract: The regulatory gene pathways that accompany loss of adipose tissue in cancer cachexia are unknown and were explored using pangenomic transcriptome profiling. Global gene expression profiles of abdominal subcutaneous adipose tissue were studied in gastrointestinal cancer patients with (n=13) or without (n=14) cachexia. Cachexia was accompanied by preferential loss of adipose tissue and decreased fat cell volume, but not number. Adipose tissue pathways regulating energy turnover were upregulated, whereas genes in pathways related to cell and tissue structure (cellular adhesion, extracellular matrix and actin cytoskeleton) were downregulated in cachectic patients. Transcriptional response elements for hepatic nuclear factor-4 (HNF4) were overrepresented in the promoters of extracellular matrix and adhesion molecule genes, and adipose HNF4 mRNA was downregulated in cachexia. Cancer cachexia is characterised by preferential loss of adipose tissue; muscle mass is less affected. Loss of adipose tissue is secondary to a decrease in adipocyte lipid content and associates with changes in the expression of genes that regulate energy turnover, cytoskeleton and extracellular matrix, which suggest high tissue remodelling. Changes in gene expression in cachexia are reciprocal to those observed in obesity, suggesting that regulation of fat mass at least partly corresponds to two sides of the same coin.

An AMP-activated protein kinase-stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice.

Abstract: Cachexia represents a fatal energy-wasting syndrome in a large number of patients with cancer that mostly results in a pathological loss of skeletal muscle and adipose tissue. Here we show that tumor cell exposure and tumor growth in mice triggered a futile energy-wasting cycle in cultured white adipocytes and white adipose tissue (WAT), respectively. Although uncoupling protein 1 (Ucp1)-dependent thermogenesis was dispensable for tumor-induced body wasting, WAT from cachectic mice and tumor-cell-supernatant-treated adipocytes were consistently characterized by the simultaneous induction of both lipolytic and lipogenic pathways. Paradoxically, this was accompanied by an inactivated AMP-activated protein kinase (Ampk), which is normally activated in peripheral tissues during states of low cellular energy. Ampk inactivation correlated with its degradation and with upregulation of the Ampk-interacting protein Cidea. Therefore, we developed an Ampk-stabilizing peptide, ACIP, which was able to ameliorate WAT wasting in vitro and in vivo by shielding the Cidea-targeted interaction surface on Ampk. Thus, our data establish the Ucp1-independent remodeling of adipocyte lipid homeostasis as a key event in tumor-induced WAT wasting, and we propose the ACIP-dependent preservation of Ampk integrity in the WAT as a concept in future therapies for cachexia.

Lipid metabolism in cancer

Abstract: Lipids form a diverse group of water-insoluble molecules that include triacylglycerides, phosphoglycerides, sterols and sphingolipids. They play several important roles at cellular and organismal levels. Fatty acids are the major building blocks for the synthesis of triacylglycerides, which are mainly used for energy storage. Phosphoglycerides, together with sterols and sphingolipids, represent the major structural components of biological membranes. Lipids can also have important roles in signalling, functioning as second messengers and as hormones. There is increasing evidence that cancer cells show specific alterations in different aspects of lipid metabolism. These alterations can affect the availability of structural lipids for the synthesis of membranes, the synthesis and degradation of lipids that contribute to energy homeostasis and the abundance of lipids with signalling functions. Changes in lipid metabolism can affect numerous cellular processes, including cell growth, proliferation, differentiation and motility. This review will examine some of the alterations in lipid metabolism that have been reported in cancer, at both cellular and organismal levels, and discuss how they contribute to different aspects of tumourigenesis.

Genome-wide gene-based analyses of weight loss interventions identify a potential role for NKX6.3 in metabolism.

Abstract: Hundreds of genetic variants have been associated with Body Mass Index (BMI) through genome-wide association studies (GWAS) using observational cohorts. However, the genetic contribution to efficient weight loss in response to dietary intervention remains unknown. We perform a GWAS in two large low-caloric diet intervention cohorts of obese participants. Two loci close to NKX6.3/MIR486 and RBSG4 are identified in the Canadian discovery cohort (n = 1166) and replicated in the DiOGenes cohort (n = 789). Modulation of HGTX (NKX6.3 ortholog) levels in Drosophila melanogaster leads to significantly altered triglyceride levels. Additional tissue-specific experiments demonstrate an action through the oenocytes, fly hepatocyte-like cells that regulate lipid metabolism. Our results identify genetic variants associated with the efficacy of weight loss in obese subjects and identify a role for NKX6.3 in lipid metabolism, and thereby possibly weight control. Individuals show large variability in their capacity to lose weight and maintain this weight. Here, the authors perform GWAS in two weight loss intervention cohorts and identify two genetic loci associated with weight loss that are taken forward for Bayesian fine-mapping and functional assessment in flies.

Adipose-derived circulating miRNAs regulate gene expression in other tissues

Abstract: Adipose tissue is a major site of energy storage and has a role in the regulation of metabolism through the release of adipokines. Here we show that mice with an adipose-tissue-specific knockout of the microRNA (miRNA)-processing enzyme Dicer (ADicerKO), as well as humans with lipodystrophy, exhibit a substantial decrease in levels of circulating exosomal miRNAs. Transplantation of both white and brown adipose tissue-brown especially-into ADicerKO mice restores the level of numerous circulating miRNAs that are associated with an improvement in glucose tolerance and a reduction in hepatic Fgf21 mRNA and circulating FGF21. This gene regulation can be mimicked by the administration of normal, but not ADicerKO, serum exosomes. Expression of a human-specific miRNA in the brown adipose tissue of one mouse in vivo can also regulate its 3' UTR reporter in the liver of another mouse through serum exosomal transfer. Thus, adipose tissue constitutes an important source of circulating exosomal miRNAs, which can regulate gene expression in distant tissues and thereby serve as a previously undescribed form of adipokine.

Cancer cachexia: understanding the molecular basis

Abstract: Cancer cachexia is a devastating, multifactorial and often irreversible syndrome that affects around 50-80% of cancer patients, depending on the tumour type, and that leads to substantial weight loss, primarily from loss of skeletal muscle and body fat. Since cachexia may account for up to 20% of cancer deaths, understanding the underlying molecular mechanisms is essential. The occurrence of cachexia in cancer patients is dependent on the patient response to tumour progression, including the activation of the inflammatory response and energetic inefficiency involving the mitochondria. Interestingly, crosstalk between different cell types ultimately seems to result in muscle wasting. Some of the recent progress in understanding the molecular mechanisms of cachexia may lead to new therapeutic approaches.