Adipose tissue,the immune system and exercise fatigue: how activated lymphocytes compete for lipids

Adipose depots that contain lymph nodes, and probably intermuscular fat in skeletal and cardiac muscle, are specialized to provision adjacent tissue in a paracrine mode. Perinodal adipocytes respond selectively to various cytokines and incorporate proportionately more polyunsaturated fatty acids. Lipolysis in the adipocytes of node-containing depots can be stimulated via inflammation of the enclosed lymph nodes. Repeated immune stimulation elicits properties characteristic of perinodal adipocytes in those elsewhere in the same depot, and hours later in other node-containing depots, but not in nodeless depots. Such site-specific properties of adipose tissue enable partitioning of dietary and metabolic supplies of fatty acids between competing tissues. Local interactions emancipate the peripheral immune system from competing with other tissues for lipids during immune responses, and may be especially important during periods of high demand, such as strenuous exercise. Biopsies of subcutaneous adipose tissue from sites remote from lymph nodes do not adequately represent the composition of fatty acids available to the immune system in situ, and perhaps that supplied to other tissues. Intermuscular fat in skeletal and cardiac muscle may also indicate paracrine relationships between adipocytes and "end-user" tissues. The concept of paracrine interactions between certain adipocytes and "user" tissue may account for the widespread contiguity between these tissues in vivo.     

Hormone-sensitive lipase-independent adipocyte lipolysis during beta-adrenergic stimulation, fasting, and dietary fat loading

In white adipose tissue, lipolysis can occur by hormone-sensitive lipase (HSL)-dependent or HSL-independent pathways. To study HSL-independent lipolysis, we placed HSL-deficient mice in conditions of increased fatty acid flux: beta-adrenergic stimulation, fasting, and dietary fat loading. Intraperitoneal administration of the beta(3)-adrenergic agonist CL-316243 caused a greater increase in nonesterified fatty acid level in controls (0.33 +/- 0.05 mmol/l) than in HSL(-/-) mice (0.12 +/- 0.01 mmol/l, P < 0.01). Similarly, in isolated adipocytes, lipolytic response to CL-316243 was greatly reduced in HSL(-/-) mice compared with controls. Fasting for 相似文献   

Site-specific differences in the action of NRTI drugs on adipose tissue incubated in vitro with lymphoid cells,and their interaction with dietary lipids

Existing theories of the origin of HIV-related adipose tissue redistribution syndrome cannot adequately explain simultaneous hypertrophy of certain depots and atrophy of others, or its occasional occurrence in untreated HIV infection. These experiments explore the hypothesis that hypertrophy of lymphoid tissue-containing adipose depots arises from drug-induced disruption to local interactions between perinodal adipocytes and activated lymphoid cells. Guinea pigs were fed on plain or lipid-supplemented (10% suet, sunflower or fish oil) chow ad libitum or restricted, and the popliteal lymph nodes were activated by repeated injection of lipopolysaccharide. Explants of perinodal and other samples from popliteal, mesentery, omentum and nodeless perirenal and epididymal depots were incubated with lymphoid cells and zidovudine, didanosine, lamivudine or stavudine at physiological concentrations (0.1-1 microg/ml) or interleukin-10 and interleukin-6, and basal and maximum lipolysis was measured. All drugs increased lipolysis from perinodal adipocytes, especially mesenteric, though less than exogenous cytokines. Effects on adipocytes from non-perinodal sites and nodeless depots were minimal. The sunflower-oil diet enhanced, and the fish-oil and restricted diets reduced, these effects. We conclude that these NRTI antiretroviral drugs modulate the local interactions between perinodal adipocytes and activated lymphoid cells. Local interactions, and hence the selective hypertrophy of node-containing adipose depots, may be curtailed by dietary manipulation.     

The activation of the adipose tissue associated with lymph nodes during the early stages of an immune response

The effects of repeated local immune challenges with lipopolysaccharide (LPS) over 24 h on basal and noradrenaline-stimulated lipolysis and the development of sensitivity to interleukin-4 and tumour necrosis factor-alpha in adipocytes associated with lymph nodes were studied in adult guinea-pigs. Properties characteristic of perinodal adipocytes appeared in adipocytes at least 10 mm from the locally stimulated popliteal lymph node within 12 h, and in other node-containing depots over 24 h. All effects appeared first in perinodal adipocytes and spread as though in response to signals emanating from the enclosed lymph node. The popliteal depot was more completely activated than the mesenteric, but its maximum rate of lipolysis/100 adipocytes was lower. None of the pre-treatments in vivo, nor incubation with cytokines in vitro modulated lipolysis in adipocytes from the nodeless perirenal depot. The sensitivity of the perinodal adipocytes to cytokines changed within 3 h of immune stimulation, preceding detectable increases in lipolysis. Cytokine-stimulated and noradrenaline-stimulated lipolysis sum, suggesting separate pathways. We conclude that sustained local activation of a single popliteal lymph node recruits additional adipocytes in node-containing depots only. Signals spread from lymph nodes to surrounding adipocytes, but the time courses of activation of adipocytes and their maximum responses differ between the mesenteric and popliteal depots.     

Generation of Lymph Node-fat Pad Chimeras for the Study of Lymph Node Stromal Cell Origin

The stroma is a key component of the lymph node structure and function. However, little is known about its origin, exact cellular composition and the mechanisms governing its formation. Lymph nodes are always encapsulated in adipose tissue and we recently demonstrated the importance of this relation for the formation of lymph node stroma. Adipocyte precursor cells migrate into the lymph node during its development and upon engagement of the Lymphotoxin-b receptor switch off adipogenesis and differentiate into lymphoid stromal cells (Bénézech et al.¹⁴). Based on the lymphoid stroma potential of adipose tissue, we present a method using a lymph node/fat pad chimera that allows the lineage tracing of lymph node stromal cell precursors. We show how to isolate newborn lymph nodes and EYFP⁺ embryonic adipose tissue and make a LN/ EYFP⁺ fat pad chimera. After transfer under the kidney capsule of a host mouse, the lymph node incorporates local adipose tissue precursor cells and finishes its formation. Progeny analysis of EYFP⁺ fat pad cells in the resulting lymph nodes can be performed by flow-cytometric analysis of enzymatically digested lymph nodes or by immunofluorescence analysis of lymph nodes cryosections. By using fat pads from different knockout mouse models, this method will provide an efficient way of analyzing the origin of the different lymph node stromal cell populations.     

Is there an optimal dose for dietary linoleic acid? Lessons from essential fatty acid deficiency supplementation and adipocyte functions in rats

Differential effects of n-3 and n-6 polyunsaturated fatty acids (PUFAs) have been demonstrated on adipose tissue physiology. Facing to the widely recognized beneficial effects of n-3 PUFAs, the n-6 PUFA effects remain controversial. Thus, we further analyzed the linoleic acid (LA) influence on adipocyte functions. To this aim, we treated by LA supplementation at three distinct doses (1, 2.5, or 5 % of energy intake) rats with essential fatty acids deficiency (EFAD). PUFA composition was determined in blood and white adipose tissue (WAT), while lipolytic and lipogenic activities were measured in isolated adipocytes. EFAD rats exhibited reduced WAT mass and increased EFAD biomarkers. WAT mass was completely recovered after supplementation, irrespective of LA dose. However, neither body mass nor EFAD biomarkers returned to control with 1 % LA, while LA abundance doubled in adipocytes from rats supplemented with 5 % LA. Regarding lipolysis, 2.5 % LA normalized the EFAD-induced alterations. A trend to decrease the maximal stimulation of lipolysis was observed with 1 and 5 % LA. Regarding lipogenesis, the lower and higher LA doses increased basal activity and hampered insulin to further stimulate glucose incorporation into lipids whereas 2.5 % LA normalized the basal or insulin-stimulated levels. Our results show that dietary linoleate at 2.5 % restored anatomical, biochemical, and functional disturbances induced by EFAD. At higher dose, LA tended to reduce triacylglycerol breakdown, to increase triacylglycerol assembly, and to provoke insulin resistance. Therefore, LA influence on adipocyte functions does not appear to follow a typical dose–response relationship, adding further complexity to the definition of its dietary requirement.     

Paracrine interactions of mammalian adipose tissue

Adipose tissue develops in and/or around most lymphoid tissues in mammals and birds. Early reports of this widespread association and hypotheses for its functional basis were long ignored in the planning of in vitro studies and the interpretation of in vivo results. Biochemical studies on rodent tissues reveal many site-specific properties of adipocytes anatomically associated with lymph nodes and omental milky spots that equip them to interact locally with lymphoid cells. The paracrine interactions are strongest for the most readily activated lymph nodes and are modulated by dietary lipids. Perinodal adipocytes contribute less than those in the large nodeless depots to whole-body lipid supplies during fasting. Observations on wild animals show that perinodal adipose tissue is selectively conserved even in starvation but does not enlarge greatly in natural obesity. Such paracrine provisioning of peripheral immune responses improves their efficiency and emancipates activated lymphocytes from competition with other tissues for blood-borne nutrients. The relationship is found in extant protherians and metatherians, so it almost certainly arose early in the evolution of mammals, possibly as part of the metabolic reorganisation associated with homeothermy, viviparity, and lactation. Prolonged disruption to paracrine interactions between lymphoid and adipose tissue may contribute to the HIV-associated adipose redistribution syndrome, causing selective hypertrophy of the mesentery, omentum, and other adipose depots that contain much activated lymphoid tissue. Skeletal and cardiac muscle may also have paracrine relationships with anatomically associated adipose tissue, but interactions between contiguous tissues have not been demonstrated directly.     

Changes in lymphokine receptor expression and fatty acid composition of phospholipids and triacylglycerols in rat adipocytes associated with lymph nodes following a transient immune challenge

Single-photon counting fluorimetry was used to record the time course of the expression of interleukin-10 receptors labelled with fluorescent antibodies on the surface of adipocytes over 24h, following an immune challenge to the rat popliteal lymph node. Homologous perinodal and remote-from-node samples from the stimulated and unstimulated popliteal depots were compared in rats fed on plain chow and chow supplemented with 10% w/w suet, fish or vegetable oils. Receptor expression was maximal 6 h after stimulation, and returned to baseline after 24 h, and was similar in the stimulated and unstimulated depots. Fewer receptors were elicited in tissues from rats fed lipid-supplemented diets compared with the control diet, with fewest of all following the fish oil diet. These data suggest that interleukin-10 is involved in local interactions between perinodal adipocytes and lymph node lymphoid cells. Both triacylglycerols and phospholipids contained more polyunsaturates and fewer saturates in perinodal adipose tissue than in samples from sites not associated with lymphoid tissue. These data are consistent with paracrine interactions between perinodal adipocytes and activated lymphoid cells.     

Efficient in vitro adipocyte model of long-term lipolysis: A tool to study the behavior of lipophilic compounds

The triglycerides (TGs) stored in the white adipose tissue are mobilized during periods of negative energy balance. To date, there is no in vitro model of adipocytes imitating a long period of negative energy balance in which triglycerides are highly mobilized. Such model would allow studying the mobilization of TGs and lipophilic compounds trapped within the adipose tissue (e.g., pollutants and vitamins). The present study aims at developing a performing long-term in vitro lipolysis in adipocytes, resulting in a significant decrease of TG stores. Lipolysis was induced on differentiated rat adipocytes by a lipolytic medium with or without isoproterenol for 12 h. The condition with isoproterenol was duplicated, once with medium renewal every 3 h and once without medium renewal. Adding isoproterenol efficiently triggered lipolysis in a short time (3 h). However, a single stimulation by isoproterenol, without medium renewal, was not sufficient to reduce the TG content during a longer term (12 h). A reesterification of fatty acids occurred after a few hours of lipolysis, resulting in a novel increase of cellular lipids. Regular medium renewal combined with repeated isoproterenol stimulations led to almost emptied cells after 12 h. However, medium renewal without isoproterenol stimulation for 12 h was as efficient in terms of lipid mobilization. Our study demonstrates that, over a short-term period, isoproterenol is required to exert a significant lipolytic effect on adipocytes. During a long-term period, the presence of isoproterenol is no longer essential. Instead, medium renewal becomes the main factor involved in cell emptying. The efficiency of this protocol was demonstrated by visual tracking of the cells and by monitoring the dynamics of release of a lipophilic compound, PCB-153, from adipocytes during lipolysis.     

Mechanism of free fatty acid re-esterification in human adipocytes in vitro

Within adipose tissue, free fatty acids liberated by lipolysis may be re-esterified into newly synthesized triacylglycerol. We hypothesized that re-esterification may occur via an extracellular route, such that free fatty acids arising from lipolysis must leave the adipocyte and be taken up again before they can be re-esterified. We simultaneously measured rates of lipolysis, acylglycerol synthesis, and free fatty acid re-esterification in human adipose tissue and isolated adipocytes in vitro, utilizing a dual-isotopic technique. We manipulated incubations to increase mixing of released free fatty acids with the incubation medium. Such manipulations should decrease the probability that released free fatty acids would be taken up and re-esterified. We found that re-esterification was decreased in isolated adipocytes compared to fragments of tissue, in shaken compared to unshaken incubations, and in low adipocyte concentrations compared to high adipocyte concentrations. Rates of acylglycerol synthesis and lipolysis were unaltered by these manipulations, indicating that changes in free fatty acid re-esterification are not secondary to effects on these processes. The results are consistent with an extracellular route for free fatty acid re-esterification. Such a mechanism suggests that adipose tissue blood flow may play an important role in the regulation of free fatty acid release from adipose tissue.     

Insulin-like stimulation of glucose transport in isolated adipocytes by fatty acids

Glucose transport rate as assessed with the 3-0-Methylglucose method was significantly increased in adipocytes preincubated with aliphatic carboxylic acids. The magnitude of stimulation apparently depended on the chain length of the carboxylic acid, and was highest with palmitic acid (130%). The stimulation was additive to the effect of insulin, and reflected a decrease of km rather than an increase in vmax of the transport rate. The results suggest that fatty acids may modulate the activity of the glucose transporter, providing an insulin-dependent supply of adipose tissue with glycerol-phosphate during lipolysis for reesterification of excess fatty acids. Further, it is suggested that fatty acids mediate the stimulatory effect of catecholamines on glucose transport as observed in isolated fat cells.     

The 20-kD human growth hormone reduces body fat by increasing lipolysis and decreasing lipoprotein lipase activity

AIM: The aim of this study was to estimate the lipolytic activity of the human growth hormone variant, 20-kD human growth hormone (20K-hGH). METHODS: Obese KV-A(y) mice were given daily subcutaneous injections of 20K-hGH (0.25, 0.5, 1.0 mg/kg), 22K-hGH (0.25 mg/kg) or saline as a control for 2 weeks. Body composition (fat, water and protein), lipolysis and lipoprotein lipase (LPL) activity were measured 24 h after the final injection. RESULTS: Both growth hormone isoforms significantly reduced relative fat pad and whole body lipids. In addition, 20K-hGH produced an inhibition of LPL activity in adipose tissue and stimulated lipolysis in adipocytes. CONCLUSION: These data strongly suggest that inhibition of LPL activity in adipose tissue and stimulation of lipolysis in adipocytes by 20K-hGH treatment reduce adipose tissue mass, resulting in body fat reduction.     

Adipose tissue microenvironments during aging: Effects on stimulated lipolysis

Adipose tissue is a critical organ for nutrient sensing, energy storage and maintaining metabolic health. The failure of adipose tissue homeostasis leads to metabolic disease that is seen during obesity or aging. Local metabolic processes are coordinated by interacting microenvironments that make up the complexity and heterogeneity of the adipose tissue. Catecholamine-induced lipolysis, a critical pathway in adipocytes that drives the release of stored triglyceride as free fatty acid after stimulation, is impaired during aging. The impairment of this pathway is associated with a failure to maintain a healthy body weight, core body-temperature during cold stress or mount an immune response. Along with impairments in aged adipocytes, aging is associated with an accumulation of inflammation, immune cell activation, and increased dysfunction in the nervous and lymphatic systems within the adipose tissue. Together these microenvironments support the initiation of stimulated lipolysis and the transport of free fatty acid under conditions of metabolic homeostasis. However, during aging, the defects in these cellular systems result in a reduction in ability to stimulate lipolysis. This review will focus on how the immune, nervous and lymphatic systems interact during tissue homeostasis, review areas that are impaired with aging and discuss areas of research that are currently unclear.     

Adipose tissue: quartermaster to the lymph node garrisons

Why is mammalian adipose tissue always split into a few large depots and many small ones, widely scattered around the body? Recent research suggests that fat cells (adipocytes) in the minor depots that enclose lymph nodes could be specialised to supply immune cells with the fuel and materials they need to mount a prompt, effective response to foreign invasion. Eliminating them or disrupting their relationship with immune cells may have unforeseen consequences.     

Activin B inhibits lipolysis in 3T3-L1 adipocytes

Activin B, consisting of two inhibin βB (INHBB) subunits, is a hormone known to affect gonadal function, reproduction and fetal development. We have reported that INHBB and activin B receptors are highly expressed in adipocytes suggesting that activin B may have local effects in adipose tissue. In this study, we investigate the effect of activin B on lipolysis, measured as release of non-esterified fatty acids and free glycerol. Recombinant activin B decreased lipolysis in a concentration-dependent manner and increased intracellular triglyceride content in 3T3-L1 adipocytes. siRNA-mediated knock-down of INHBB expression increased lipolysis, and this effect was abolished by addition of recombinant activin B. In line with its inhibitory effect on lipolysis, activin B caused a down regulation of the expression of adipose triglyceride lipase and hormone sensitive lipase, key genes involved in lipolysis. In summary, we suggest that activin B is a novel adipokine that inhibits lipolysis in a paracrine or autocrine manner.     

Movement of lipolytic products to mitochondria in brown adipose tissue of young rats: an electron microscope study

Lipolysis occurred and lamellar structures with a periodicity of 40 A developed in glutaraldehyde-fixed brown adipose tissue of suckling rats when the tissue was incubated at 25 degrees C. The lamellar structures were found in capillaries, associated with chylomicrons, in intracellular channels of capillary endothelium, in extracellular space, and in channels near lipid droplets in adipocytes in tissue of fed rats injected intravenously with chylomicrons. They were also found in channels near mitochondria and inside mitochondria in adipocytes in incubated-fixed tissue of rats exposed to 4 degrees C for 2 hr or unsuckled overnight. In addition, aqueous spaces developed adjacent to lipid droplets in incubated tissue of cold-exposed and unsuckled rats. Development of lamellar structures under conditions causing lipolysis and accumulation of fatty acids in fixed tissue indicated the lamellae were composed primarily of fatty acids. We conclude that fatty acids formed by lipolysis of chylomicrons in tissue from fed rats accumulated in a continuum of the outer leaflets of cell membranes extending from capillary lumen to lipid droplets of adipocytes, and fatty acids formed by lipolysis of intracellular lipid in tissue from cold-exposed or unsuckled rats accumulated mostly in a continuum extending from lipid droplets to the interior of mitochondria. When fatty acids overcrowded the continuum in fixed tissue, they formed lamellar extensions of the continuum at different sites along its course through the tissue.     

Lipidomics of brown and white adipose tissue: Implications for energy metabolism

Adipose tissue exerts multiple vital functions that critically maintain energy balance, including storing and expending energy, as well as secreting factors that systemically modulate nutrient metabolism. Since lipids are the major constituents of the adipocytes, it is unsurprising that the lipid composition of these cells plays a critical role in maintaining their functions and communicating with other organs and cells. In both positive and negative energy balance conditions, lipids and free fatty acids secreted from adipocytes exert either beneficial or detrimental effects in other tissues, such as the liver, pancreas and muscle. The way the adipocytes communicate with other organs tightly depends on the nature of their lipidome composition. Notwithstanding, the lipidome composition of the adipocytes is affected by physiological factors such as adipocyte type, gender and age, but also by environmental cues such as diet composition, thermal stress and physical activity. Here we provide an updated overview on how the adipose tissue lipidome profile is shaped by different physiological and environmental factors and how these changes impact the way the adipocytes regulate whole-body energy metabolism.     

The role of dietary fatty acids in the pathology of metabolic syndrome

Dysfunctional lipid metabolism is a key component in the development of metabolic syndrome, a very frequent condition characterized by dyslipidemia, insulin resistance, abdominal obesity and hypertension, which are related to an elevated risk for type 2 diabetes mellitus. The prevalence of metabolic syndrome is strongly associated with the severity of obesity; its physiopathology is related to both genetics and food intake habits, especially the consumption of a high-caloric, high-fat and high-carbohydrate diet. With the progress of scientific knowledge in the field of nutrigenomics, it was possible to elucidate how the majority of dietary fatty acids influence plasma lipid metabolism and also the genes expression involved in lipolysis and lipogenesis within hepatocytes and adipocytes. The aim of this review is to examine the relevant mechanistic aspects of dietary fatty acids related to blood lipids, adipose tissue metabolism, hepatic fat storage and inflammatory process, all of them closely related to the genesis of metabolic syndrome.