Файл: Extracellular and Intracellular Signaling (книга).pdf

References

1.P. Wall, Pain: The Science of Su ering, Cambridge University Press, New York, 2000.

2.B. McEwen and E. N. Lasley, The End of Stress as We Know It, Joseph Henley Press, Washington, D.C., 2002.

3.E. J. Lien and L. L. Lien, Curr. Drug Disc. Technol., 2010, 7, 13.

4.H. V. Thiagaraj, T. C. Ortiz, M. C. Devereaux, B. Seaver, B. Hall and

K.K. Parker, Neurochem. Int., 2007, 50, 109.

5.S. A. Ritchie and J. M. Connell, Nutr. Metab. Cardiovasc. Dis., 2007, 17, 319.

6.P. E. Szmitko, H. Teoh, D. J. Stewart and S. Verma, Am. J. Physiol. Circ. Physiol., 2007, 292, H1655.

7.Y. Matsuzawa, FEBS Letts, 2006, 580, 2917.

8.I. Matias and V. Di Marzo, Trends Endocrinol. Metab., 2006, 18, 27.

9.C. G. Walker, M. G. Zariwala, M. J. Holness and M. C. Sugden, Clin. Sci., 2007, 112, 93.

10.A. G. Pittas, N. A. Joseph and A. S. Greenberg, J. Clin. Endocrinol. Metab., 2004, 89, 447.

11.M. Otero, R. Lago, R. Gomez, C. Dieguez, F. Lago, J. Go´mez-Reino and

O.Gualillo, Rheumatol., 2006, 45, 944.

a short timescale, the current world epidemic of T2DM is better explained by environmental influences or possibly epigenetic modification.21 Epidemiological studies indicate that factors influencing the prevalence of T2DM include lifestyle (e.g. inactivity and dietary macronutrient composition) and obesity,22–24 age and geographical area of residence. Of these factors obesity, defined as an excess of body fat that is deemed unhealthy for the individual and a body mass index (BMI) of over 30, is one of the most important.25 Notably, both an enhanced b-cell secretory function and a compensatory increase in b-cell mass is seen in obese individuals who do not develop T2DM; these adaptations are able to counteract the increased metabolic load and obesity-associated insulin resistance.26 In the subset of obese individuals who develop T2DM, a failure in b-cell adaptation takes place.27 We hypothesize that failure of b-cell adaptation may, in part, reflect the changes in adipose composition and function that occur as it expands.

White adipose tissue comprises a range of di erent cell types: mature adipocytes (fat cells) themselves, their immediate precursors (preadipocytes) and stroma-vascular cells including fibroblastic connective tissue cells, leucocytes and macrophages.28 In adult mammals, most of the adipose tissue mass comprises lipid-filled cells (the adipocytes) in a framework of collagen fibers. An increase in body fat is caused by a combination of increased di erentiation of preadipocytes to mature adipocytes, together with hypertrophy of mature adipocytes mainly due to increased triglyceride (TAG) storage. Thus, white adipocytes vary greatly in size, and can change their diameters by 20-fold and their volumes by several-thousand-fold to accommodate lipid. T2DM, insulin resistance and the metabolic syndrome are characterized by increased circulating FA and by increased lipolysis (breakdown) of the expanded TAG stores.

The ability of adipocytes to store FA as TAG in the fed state provides animals with a fuel store for use in time of need; in addition, sequestration of excess dietary FA in adipose tissue can improve insulin action in liver and muscle by suppressing excess FA delivery to these tissues, which can cause insulin resistance and tissue dysfunction.29 In the fed state, insulin increases adipocyte TAG storage by augmenting adipocyte glucose uptake (allowing the production of glycerol 3-phosphate for FA esterification to form TAG and the formation of FA de novo), by direct e ects to stimulate enzymes in the pathway for esterification of incoming FA, mainly generated locally via adipocyte lipoprotein lipase (LPL), and by e ects to block TAG lipolysis. Adipocyte glucose uptake and its conversion to glycerol 3-phosphate is also enhanced by activation of the peroxisome proliferator-activated receptor g(PPARg).30,31 PPARg, a ‘‘lipogenic’’ transcription factor, enhances the expression of genes involved in glucose uptake and conversion to TAG32 and also stimulates glycerol transport, glyceroneogenesis and glycerol phosphorylation.30,33

In response to lipolytic stimulation, adipocytes hydrolyze stored TAG and release FA and glycerol into the circulation. FAs are used as substrates for ATP production in a range of oxidative tissues; glycerol is used for hepatic gluconeogenesis. The contribution of glycerol to glucose production depends on the nutritional state. This may vary from 5% postprandially in humans34 and

approx. 50% in the post-absorptive state in rodents35 to 20% in humans34,36 and 490% in rodents after prolonged fasting.35 The significance of glycerol as a gluconeogenic precursor is supported by the episodic hypoglycemia observed in patients with glycerol kinase deficiency.37

As well as serving as repositories for lipid, which can be mobilized when required, adipose tissue also releases adipokines involved in the regulation of normal physiological processes (e.g. the control of vascular homeostasis, blood pressure and regulation of energy balance)26 as well as contributing to the pathology of some disease states. One adipokine, leptin, is secreted from adipose tissue in proportion to adipose mass. Leptin is thought to inhibit food intake and increase energy expenditure when healthy individuals experience chronic overnourishment. To achieve the former, leptin targets hypothalamic neurons in the arcuate and in paraventricular, dorsomedial and ventromedial nuclei. Leptin has opposing actions on two populations of arcuate neurons, one that synthesizes the appetite-promoting peptides neuropeptide Y and agoutiregulated peptide (AgRP) and a second that synthesizes anorexigenic peptides, e.g. POMC (the precursor of the appetite-suppressing peptide melanocyte stimulating hormone). Leptin stimulates POMC neurons whilst inhibiting NPY and AgRP neurons. Leptin also exerts direct e ects on peripheral tissues (including liver, pancreatic islets, skeletal muscle), a ecting peripheral energy partitioning, in particular the intracellular disposition of nutrients (storage versus degradation). The ‘‘energy-sensor’’ AMP-activated protein kinase (AMPK) orchestrates critical metabolic adaptations to reduced energy availability and is activated by leptin in peripheral tissues, in particular skeletal muscle and liver.38 Obesity is characterized by leptin resistance.39 Thus, while circulating leptin levels are elevated in obesity, its e ects to limit food intake and promote energy expenditure are blunted due to the existence of leptin resistance. This may be due to leptin receptor signaling defects, for example elevated SOCS3 expression in leptin-responsive neurons of the arcuate nucleus,39 and/or defects in leptin transport across the blood-brain barrier.40

Adiponectin is another important adipokine. Adiponectin administration ameliorates insulin resistance in mice,41 whereas adiponectin-deficient mice exhibit insulin resistance42 and diabetes. This insulin-sensitizing e ect of adiponectin, like that of leptin, involves AMPK, the activation of which increases FA oxidation acutely,43 and also augments signaling via the lipo-oxidative transcription factor PPARa.44 PPARa increases the expression of genes involved in FA uptake and oxidation.45 Enhanced insulin sensitivity in response to adiponectin arises because of increased lipid clearance from the tissue via oxidation. Low circulating levels of adiponectin and increased leptin and C-reactive protein (CRP) have recently emerged as novel diabetic risk factors.46

In obesity, there is progressive adipose-tissue infiltration by macrophages that secrete proinflammatory cytokines (e.g. tumor necrosis factor (TNF) a, IL (interleukin)-1b and IL-6). TNFa over-expression is observed in adipose tissue and muscle of obese humans47 and in adipose tissue of genetically obese insulin resistant mice. Monocyte chemoattractant protein 1 (MCP-1) is mainly secreted by macrophages present in adipose tissue; however, adipocytes themselves

also release considerable amounts of MCP-148 and adipocyte MCP-1 may be the main chemokine that causes adipose tissue infiltration by macrophages within the context of obesity and insulin resistance. Mice over-expressing MCP-1 in adipose tissue using the adipocyte aP2 promoter (aP2-MCP-1 mice) are insulin resistant and have higher adipose-tissue macrophage accumulation than control mice.49 It has been suggested that a paracrine loop exists between adipocytes and macrophages that aggravates inflammatory processes.50 Coculture of di erentiated 3T3-L1 adipocytes with RAW264 macrophages results in an upregulation of macrophage TNFa secretion and a downregulation of secretion of the insulin-sensitizing adipokine adiponectin.50

The chronic inflammatory state present locally within adipose tissue itself becomes systemic when inflammatory cytokines are released into the circula-

tion. Thus obesity is characterized by increased circulating concentrations of pro-inflammatory cytokines51–53 and acute phase proteins.54,55 Circulating

leptin concentrations are increased, probably reflecting leptin resistance, whereas adiponectin concentrations are decreased in obesity.56 TNFa can impair insulin signaling and, in obese mice, lack of TNFa function improves

insulin sensitivity and glucose homeostasis, confirming the critical role of TNFa in modulating insulin action.57,58 Knowledge of the actions of the pro-

atherogenic and inflammatory mediators (cytokines and chemokines) that are derived from adipose tissue, either from the adipocytes or from the infiltrating macrophages that are associated with increased adiposity,59 may help gain a better understanding of the pathophysiology of the chronic proinflammatory state associated with obesity.

2.3 Feedback between FA and the Adipocyte

Evidence is now accumulating that FAs generated via adipocyte TAG lipolysis have pronounced direct feedback e ects on adipocytes. Within the adipocyte itself, AMPK can be activated by cAMP-inducing agents.60 This is proposed to be a consequence of stimulated lipolysis secondary to activation of cAMPdependent protein kinase (PKA) and activation by phosphorylation of key components of the lipolytic machinery. It has been suggested that AMPK activation in adipocytes in this setting is caused by an increased AMP : ATP ratio that appears to be due, at least in part, to the re-acylation of FA released by lipolysis. AMPK activation has been suggested to be part of a mechanism to restrain the energy depletion and oxidative stress caused by excessive lipolysis.

Toll-like receptors (TLR; specifically TLR-2 and -4) constitute a molecular

link between elevated circulating FA, as found in obesity, and inflammation in insulin-sensitive tissues including adipocytes.61,62 TLR-2 and -4 bind lipid-

based structures via their long-chain saturated FA moieties.63 Saturated FA, but not unsaturated FA, induce the expression of cyclooxygenase-2 via TLR-4.63,64 The adipocyte itself is capable of mounting a classical innate immune response initiated by ligand activation of TLR-4, followed by activation of nuclear factor-kB (NF-kB), increasing proinflammatory gene expression and

cytokine release.65–67 Importantly, FA (released from hypertrophic adipocytes under conditions of lipolytic stimulation) may signal to macrophages through activation of TLR-4 and stimulation of MCP-1 release by mature adipocytes in a manner dependent on dose and class of FA.68 The production of MCP-1 by adipocytes provides a potential explanation as to how macrophages are directed into the adipose tissue from the bloodstream within the context of obesity or insulin resistance (where plasma NEFA concentrations are elevated).

FAs, acting through the adipocyte TLR-4, also stimulate the release of TNFa68,69 and, somewhat surprisingly, at physiological concentrations, influence the secretion of adiponectin. Exogenous FAs enhance the nuclear translocation of NF-kB p65 and NF-kB inhibition strongly antagonizes the proinflammatory e ects of the FAs palmitic acid and stearic acid. It has therefore been argued that there might be a paracrine or autocrine role of FA in adipocyte biology, with a key involvement of NF-kB.68

2.4Autocrine E ects of Leptin and Adiponectin in Adipocytes

Leptin’s actions are initiated by its binding to a leptin receptor, encoded by the Lept gene, a member of the interleukin-6 receptor family of cytokine receptors. There are six di erent splice variants of the leptin receptor (Ob-R). Of these ObRb – the long isoform – is required for leptin’s physiological actions. Leptin links metabolic and immune responses. Leptin levels are low in infection but high in autoimmunity, both systemically and at the site of inflammation. Immune abnormalities in obesity are reversed with energy restriction (which decreases leptin levels). Leptin levels correlate with energy status and with TNFa, which is also elevated in obesity and suppresses lymphocyte function.70

Peripheral and central responses to leptin can be intimately linked. Leptin can induce changes in the brain that, in turn, a ect TAG homeostasis in adipose tissue. Leptin signaling via phosphoinositide 3-kinase (PI3K) in the hypothalamus engages the sympathetic nervous system (SNS), resulting in signaling back to the adipocytes through the endocannabinoid system.71 Thus, infusion of leptin into the basal medial hypothalamus leads to a rapid switch from lipogenesis to lipolysis.71 This change was reflected by suppression of sterol regulatory element binding protein 1 (SREBP1), together with marked downregulation of SREBP-1c targets, including the lipogenic enzymes acetylCoA carboxylase (ACC), fatty acid synthase (FAS) and stearoyl-CoA desaturase (SCD) 1.71

White adipocytes also express leptin receptors72 allowing them to respond to their own secretions. Leptin can also exert an anti-lipogenic autocrine action on adipocytes via AMPK activation (a 7-fold higher ratio of phosphorylated to total AMPK). This depletes stored adipose-tissue TAG, an e ect proposed to reflect oxidation of lipolytically generated FA in situ.73 This e ect is predicted not to be observed in adipose tissue of db/db mice. db/db mice are obese, insulin resistant and hyperleptinemic, a phenotype that develops as a result of leptin