Oxidative stress and lipid peroxidation by-products at the crossroad between adipose organ dysregulation and obesity-linked insulin resistance (original) (raw)
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Free Radical Biology and Medicine, 2013
Obesity has been proposed as an energy balance disorder in which the expansion of adipose tissue (AT) leads to unfavorable health outcomes. Even though adiposity represents the most powerful driving force for the development of insulin resistance (IR) and type 2 diabetes, mounting evidence points to "adipose dysregulation", rather than fat mass accrual per se, as a key pathophysiological trigger of the obesitylinked metabolic complications. The dysfunctional fat, besides hypertrophic adipose cells and inflammatory cues, displays a reduced ability to form new adipocytes from the undifferentiated precursor cells (ie, the preadipocytes). The failure of adipogenesis poses a "diabetogenic" milieu either by promoting the ectopic overflow/deposition of lipids in non-adipose targets (lipotoxicity) or by inducing a dysregulated secretion of different adipose-derived hormones (ie, adipokines and lipokines). This novel and provocative paradigm ("expandability hypothesis") further extends current "adipocentric view" implicating a reduced adipogenic capacity as a missing link between "unhealthy" fat expansion and impairment of metabolic homeostasis.
Free Radical Biology and Medicine, 2012
The expansion of adipose tissue (AT) is, by definition, a hallmark of obesity. However, not all increases in fat mass are associated with pathophysiological cues. Indeed, whereas a "healthy" fat mass accrual, mainly in the subcutaneous depots, preserves metabolic homeostasis, explaining the occurrence of the metabolically healthy obese phenotype, "unhealthy" AT expansion is importantly associated with insulin resistance/type 2 diabetes and the metabolic syndrome. The development of a dysfunctional adipose organ may find mechanistic explanation in a reduced ability to recruit new and functional (pre)adipocytes from undifferentiated precursor cells. Such a failure of the adipogenic process underlies the "AT expandability" paradigm. The inability of AT to expand further to store excess nutrients, rather than obesity per se, induces a diabetogenic milieu by promoting the overflow and the ectopic deposition of fatty acids in insulin-dependent organs (i.e., lipotoxicity), the secretion of various metabolically detrimental adipose-derived hormones (i.e., adipokines and lipokines), and the occurrence of local and systemic inflammation and oxidative stress. Hitherto, fatty acids (i.e., lipokines) and the oxidation by-products of cholesterol and polyunsaturated fatty acids, such as nonenzymatic oxysterols and reactive aldehyde species, respectively, emerge as key modulators of (pre)adipocyte signaling through Wnt/βcatenin and MAPK pathways and potential regulators of glucose homeostasis. These and other mechanistic insights linking adipose dysfunction, oxidative stress, and impairment of glucose homeostasis are discussed in this review article, which focuses on adipose peroxidation as a potential instigator of, and a putative therapeutic target for, obesity-associated metabolic dysfunctions.
Journal of Cellular Biochemistry, 2011
Acyl-ghrelin (AG), desacyl-ghrelin (DAG) and obestatin are all derived from the same gene transcript; however their plasma levels do not necessarily change in parallel. The influence of these peptides towards the development of obesity and their direct effects on adipocyte physiology has not been thoroughly investigated. This study was designed to evaluate the direct effects of peptides of the ghrelin family on preadipocyte proliferation, differentiation and adipocyte lipid and glucose metabolism in 3T3-L1 cells. 3T3 cells were treated with physiological peptide concentrations for 1 h to 9 days, and the relevant assays measured. In preadipocytes, AG, GHRP-6 and DAG stimulated proliferation, measured as 3 H-thymidine incorporation (up to 200%, P < 0.05), while all peptides stimulated differentiation (up to 300%, P < 0.01) as compared to standard differentiation conditions. In adipocytes, FA uptake was increased in a concentration-dependent manner especially with obestatin (three-to fourfold, P < 0.001) and DAG (three-to fivefold, P < 0.001). By contrast, glucose transport was unchanged. DAG and obestatin significantly decreased lipolysis measured as non-esterified fatty acid and glycerol release by 50%, P < 0.05-0.01 and 51%, P < 0.01, respectively. Interestingly, DAG stimulation of FA uptake was blocked with GHSR1 antagonist (D-lys 3 )-GHRP-6 ( P < 0.05), phospholipase C inhibitor U73122 and phosphatidylinositol-3-kinase inhibitor wortmannin ( P < 0.001). Finally, in omental but not subcutaneous human adipose tissue, GHSR1 correlated with BMI (r ¼ 0.549, P < 0.05) and insulin (r ¼ 0.681, P < 0.01). Taken together, these results suggest that ghrelin-related peptides may directly affect adipose tissue metabolism.
Modulation of Lipid Metabolism by Energy Status of Adipocytes
Annals of the New York Academy of Sciences, 2006
It is becoming evident that insulin resistance of white adipose tissue is a major factor underlying the cardiovascular risk of obesity. Impaired fat storage rather than altered glucose metabolism in adipocytes probably contributes to development of insulin resistance in muscle and other tissues, in particular via increased delivery of nonesterified fatty acids into circulation. Lipid metabolism of adipose tissue is affected by the energy status of fat cells.
Ghrelin action in the brain controls adipocyte metabolism
2006
Many homeostatic processes, including appetite and food intake, are controlled by neuroendocrine circuits involving the CNS. The CNS also directly regulates adipocyte metabolism, as we have shown here by examining central action of the orexigenic hormone ghrelin. Chronic central ghrelin infusion resulted in increases in the glucose utilization rate of white and brown adipose tissue without affecting skeletal muscle. In white adipocytes, mRNA expression of various fat storage-promoting enzymes such as lipoprotein lipase, acetyl-CoA carboxylase a, fatty acid synthase, and stearoyl-CoA desaturase-1 was markedly increased, while that of the rate-limiting step in fat oxidation, carnitine palmitoyl transferase-1a, was decreased. In brown adipocytes, central ghrelin infusion resulted in lowered expression of the thermogenesis-related mitochondrial uncoupling proteins 1 and 3. These ghrelin effects were dose dependent, occurred independently from ghrelin-induced hyperphagia, and seemed to be mediated by the sympathetic nervous system. Additionally, the expression of some fat storage enzymes was decreased in ghrelin-deficient mice, which led us to conclude that central ghrelin is of physiological relevance in the control of cell metabolism in adipose tissue. These results unravel the existence of what we believe to be a new CNS-based neuroendocrine circuit regulating metabolic homeostasis of adipose tissue. Nonstandard abbreviations used: ACC, acetyl-CoA carboxylase a; BAT, brown adipose tissue; CPT-1a, carnitine palmitoyl transferase-1a; FAS, fatty acid synthase; ghrelin-ad lib, ghrelin-infused, ad libitum-fed; ghrelin-pf, ghrelin-infused, pair-fed to controls; LPL, lipoprotein lipase; NPY, neuropeptide Y; RQ, respiratory quotient; SCD1, stearoyl-CoA desaturase-1; TG, triglyceride; TKO, triple β1-, β2-, and β3-adrenoceptor knockout; UCP, uncoupling protein; WAT, white adipose tissue.
Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes
Nature Reviews Molecular Cell Biology, 2008
Acquired resistance to the action of insulin to stimulate glucose transport in skeletal muscle is associated with obesity and promotes the development of type 2 diabetes. In skeletal muscle, insulin resistance can result from high levels of circulating fatty acids that disrupt insulin signalling pathways. However, the severity of insulin resistance varies greatly among obese people. Here we postulate that this variability might reflect differences in levels of lipid-droplet proteins that promote the sequestration of fatty acids within adipocytes in the form of triglycerides, thereby lowering exposure of skeletal muscle to the inhibitory effects of fatty acids.
The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism reg
2001
The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Physiol Endocrinol Metab 280: E827-E847, 2001.-The ability to ensure continous availability of energy despite highly variable supplies in the environment is a major determinant of the survival of all species. In higher organisms, including mammals, the capacity to efficiently store excess energy as triglycerides in adipocytes, from which stored energy could be rapidly released for use at other sites, was developed. To orchestrate the processes of energy storage and release, highly integrated systems operating on several physiological levels have evolved. The adipocyte is no longer considered a passive bystander, because fat cells actively secrete many members of the cytokine family, such as leptin, tumor necrosis factor-␣, and interleukin-6, among other cytokine signals, which influence peripheral fuel storage, mobilization, and combustion, as well as energy homeostasis. The existence of a network of adipose tissue signaling pathways, arranged in a hierarchical fashion, constitutes a metabolic repertoire that enables the organism to adapt to a wide range of different metabolic challenges, such as starvation, stress, infection, and short periods of gross energy excess.
Adipose Tissue: A Regulator for Obesity and Its Complications
International Journal of Biochemistry Research & Review, 2016
Adipose tissue is a key player in whole body metabolism and excess adipose tissue poses a major risk factor for the development of metabolic disorders such as type 2 diabetes. In response to nutritional overload, de novo adipocyte differentiation can serve as an adaptive mechanism by increasing the storage capacity of adipose tissue and maintaining normal adipocyte function. This in turn prevents systemic lipid overload, which is a major cause for insulin resistance. Adipose tissue is of two types; the fat storing white adipose tissue and the thermogenic brown adipose tissue. While the former is implicated in obesity, insulin resistance and diabetes, the latter is a physiological anti-obesogenic and antidiabetic through adaptive thermogenesis by uncouplers proteins. Obesity results from the imbalanced energy intake for expenditure with excessive fat accumulation in adipose tissue. Obesity is associated with numerous metabolic disorders, including hyperlipidemia, diabetes mellitus, hypertension, stroke, osteoarthritis, infertility and certain types of cancer. Obesity is associated with chronic subclinical inflammation in which the metabolism of Rahiman et al.; IJBcRR, 9(1): 1-9, 2016; Article no.IJBcRR.18221 2 adipose tissue plays an important role. The adipose tissue is an endocrine organ which has a fundamental role in metabolic, inflammatory, cardiovascular homeostatic regulation through lipogenesis, lipolysis, steroidogeneis, and secretion of several biologically active adipokines and pro-inflammatory cytokines with diverse protein structures and functions. This review article will mainly focus on the pathophysiological changes of adipose tissue fat during obesity in relation to energy expenditure towards prevention or development of obesity and its complications.