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• W2000221817 abstract "High-fat diets cause peripheral leptin resistance, and dietary lipid composition affects sensitivity to leptin. We examined the role of n-3 polyunsaturated fatty acid (PUFA) in peripheral leptin resistance. Dietary PUFAs (0.4% wt/wt) caused insensitivity to peripherally but not intracerebroventricularly administered leptin. n-3 PUFA increased body weight, associated with a significant reduction of leptin concentration in the cerebrospinal fluid. Dietary n-3 PUFA reduced transport of endogenous or exogenously administered leptin into the brain, associated with increased expression of hypothalamic occludin, but caused no change in expression of leptin receptors, proteins associated with leptin signaling or other tight junction proteins. Continuous intracerebroventricular infusion of an antisense morpholino oligonucleotide targeted to occludin mRNA reversed n-3 PUFA-induced insensitivity to peripherally administered leptin. We conclude that n-3 PUFA induces peripheral leptin resistance via an increase in the expression of hypothalamic occludin, reducing paracellular transport of leptin into the brain. High-fat diets cause peripheral leptin resistance, and dietary lipid composition affects sensitivity to leptin. We examined the role of n-3 polyunsaturated fatty acid (PUFA) in peripheral leptin resistance. Dietary PUFAs (0.4% wt/wt) caused insensitivity to peripherally but not intracerebroventricularly administered leptin. n-3 PUFA increased body weight, associated with a significant reduction of leptin concentration in the cerebrospinal fluid. Dietary n-3 PUFA reduced transport of endogenous or exogenously administered leptin into the brain, associated with increased expression of hypothalamic occludin, but caused no change in expression of leptin receptors, proteins associated with leptin signaling or other tight junction proteins. Continuous intracerebroventricular infusion of an antisense morpholino oligonucleotide targeted to occludin mRNA reversed n-3 PUFA-induced insensitivity to peripherally administered leptin. We conclude that n-3 PUFA induces peripheral leptin resistance via an increase in the expression of hypothalamic occludin, reducing paracellular transport of leptin into the brain. The ob gene product leptin was discovered through study of genetically obese (ob/ob) mice (Zhang et al., 1994Zhang Y. Proenca R. Maffei M. Barone M. Leopold L. Friedman J.M. Positional cloning of the mouse obese gene and its human homologue.Nature. 1994; 372: 425-432Crossref PubMed Scopus (11385) Google Scholar). Leptin is a 16 kDa adipokine that regulates feeding behavior, reproduction, and immune function (Campfield et al., 1995Campfield L.A. Smith F.J. Guisez Y. Devos R. Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks.Science. 1995; 269: 546-549Crossref PubMed Scopus (3025) Google Scholar, Halaas et al., 1995Halaas J.L. Gajiwala K.S. Maffei M. Cohen S.L. Chait B.T. Rabinowitz D. Lallone R.L. Burley S.K. Friedman J.M. Weight-reducing effects of the plasma protein encoded by the ob gene.Science. 1995; 269: 543-546Crossref PubMed Scopus (4138) Google Scholar, Cunningham et al., 1999Cunningham M.J. Clifton D.K. Steiner R.A. Leptin’s actions on the reproductive axis: perspectives and mechanisms.Biol. Reprod. 1999; 60: 216-222Crossref PubMed Scopus (425) Google Scholar, Okamoto et al., 2000Okamoto S. Irie Y. Ishikawa I. Kimura K. Masayuki S. Central leptin suppresses splenic lymphocyte functions through activation of the corticotropin-releasing hormone-sympathetic nervous system.Brain Res. 2000; 855: 192-197Crossref PubMed Scopus (29) Google Scholar). Leptin, released from white adipose tissues, acts on the arcuate nucleus of the hypothalamus to inhibit appetite, to stimulate sympathetic nerve activities, and to cause body weight reduction in rodents (Campfield et al., 1995Campfield L.A. Smith F.J. Guisez Y. Devos R. Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks.Science. 1995; 269: 546-549Crossref PubMed Scopus (3025) Google Scholar, Halaas et al., 1995Halaas J.L. Gajiwala K.S. Maffei M. Cohen S.L. Chait B.T. Rabinowitz D. Lallone R.L. Burley S.K. Friedman J.M. Weight-reducing effects of the plasma protein encoded by the ob gene.Science. 1995; 269: 543-546Crossref PubMed Scopus (4138) Google Scholar). Leptin is also known to stimulate secretion of LH and FSH from the pituitary gland via hypothalamic GnRH release and thereby activate the reproductive axis (Cunningham et al., 1999Cunningham M.J. Clifton D.K. Steiner R.A. Leptin’s actions on the reproductive axis: perspectives and mechanisms.Biol. Reprod. 1999; 60: 216-222Crossref PubMed Scopus (425) Google Scholar). The central administration of leptin is known to suppress specific functions of the lymphocytes via the activation of the sympathetic nervous system (Okamoto et al., 2000Okamoto S. Irie Y. Ishikawa I. Kimura K. Masayuki S. Central leptin suppresses splenic lymphocyte functions through activation of the corticotropin-releasing hormone-sympathetic nervous system.Brain Res. 2000; 855: 192-197Crossref PubMed Scopus (29) Google Scholar). Leptin is transported across the blood-brain barrier (BBB) and binds to its specific receptor, which belongs to the class I cytokine receptor family. The long form of the leptin receptor (OB-Rb) is activated by the formation of a homodimer. The intracellular signal transduction of leptin is mediated predominantly through the phosphorylation of the Janus kinase 2-signal transducer and activator of transcription-3 (STAT-3) pathway (Tartaglia et al., 1995Tartaglia L.A. Dembski M. Weng X. Deng N. Culpepper J. Devos R. Richards G.J. Campfield L.A. Clark F.T. Deeds J. Identification and expression cloning of a leptin receptor, OB-R.Cell. 1995; 83: 263-271Abstract Full Text PDF Scopus (3159) Google Scholar, Vaisse et al., 1996Vaisse C. Halaas J.L. Horvath C.M. Darnell Jr., J.E. Stoffel M. Friedman J.M. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice.Nat. Genet. 1996; 14: 95-97Crossref PubMed Scopus (926) Google Scholar). The SOCS-3 (suppressor of cytokine signaling-3) pathway is a leptin-inducible inhibitor of leptin signaling and has been suggested as a possible mediator of leptin resistance in obesity (Bjorbaek et al., 1998Bjorbaek C. Elmquist J.K. Frantz J.D. Shoelson S.E. Flier J.S. Identification of SOCS-3 as a potential mediator of central leptin resistance.Mol. Cell. 1998; 1: 619-625Abstract Full Text Full Text PDF PubMed Scopus (825) Google Scholar). In humans, the concentration of circulating leptin is well correlated with body mass index (BMI), percentage of body fat, and total body fat weight (Considine et al., 1996Considine R.V. Sinha M.K. Heiman M.L. Kriauciunas A. Stephens T.W. Nyce M.R. Ohannesian J.P. Marco C.C. McKee L.J. Bauer T.L. Caro J.F. Serum immunoreactive-leptin concentrations in normal-weight and obese humans.N. Engl. J. Med. 1996; 334: 292-295Crossref PubMed Scopus (5382) Google Scholar, Shimizu et al., 1997Shimizu H. Shimomura Y. Hayashi R. Ohtani K. Sato N. Futawatari T. Mori M. Serum leptin concentration is associated with total body fat mass, but not abdominal fat distribution.Int. J. Obes. Relat. Metab. Disord. 1997; 21: 536-541Crossref PubMed Scopus (107) Google Scholar) but is not related to body fat distribution (Shimizu et al., 1997Shimizu H. Shimomura Y. Hayashi R. Ohtani K. Sato N. Futawatari T. Mori M. Serum leptin concentration is associated with total body fat mass, but not abdominal fat distribution.Int. J. Obes. Relat. Metab. Disord. 1997; 21: 536-541Crossref PubMed Scopus (107) Google Scholar). Restriction of dietary intake is also known to result in a reduction of serum leptin concentration in humans (Shimizu et al., 1997Shimizu H. Shimomura Y. Hayashi R. Ohtani K. Sato N. Futawatari T. Mori M. Serum leptin concentration is associated with total body fat mass, but not abdominal fat distribution.Int. J. Obes. Relat. Metab. Disord. 1997; 21: 536-541Crossref PubMed Scopus (107) Google Scholar). Although obese patients exhibit high concentrations of circulating leptin, administration of endogenous leptin clearly fails to inhibit appetite in these patients. This indicates that these patients were resistant to leptin. A randomized clinical trial confirmed that obese people are resistant to exogenously administered leptin and that high doses of leptin are required to reduce body weight in obese patients (Heymsfield et al., 1999Heymsfield S.B. Greenberg A.S. Fujioka K. Dixon R.M. Kushner R. Hunt T. Lubina J.A. Patane J. Self B. Hunt P. McCamish M. Recombinant leptin for weight loss in obese and lean adults. A randomized, controlled, dose-escalation trial.JAMA. 1999; 282: 1568-1575Crossref PubMed Scopus (1120) Google Scholar). The ratio of cerebrospinal leptin concentration to blood leptin concentration is clearly lower in obese people than in lean subjects (Caro et al., 1996Caro J.F. Kolaczynski J.W. Nyce M.R. Ohannesian J.P. Opentanova I. Goldman W.H. Lynn R.B. Zhang P.-L. Sinha M.K. Considine R.V. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance.Lancet. 1996; 348: 159-161Abstract Full Text Full Text PDF PubMed Scopus (1039) Google Scholar, Schwartz et al., 1996aSchwartz M.W. Peskind E. Raskind M. Boyko E.J. Porte Jr., D. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans.Nat. Med. 1996; 2: 589-593Crossref PubMed Scopus (873) Google Scholar), indicating that the transport of leptin into the brain might be interrupted in human obesity. These clinical data strongly indicate that obese patients should exhibit peripheral leptin resistance. However, the existence of peripheral leptin resistance has yet to be confirmed, and the mechanisms involved have yet to be elucidated. Moreover, high-fat diets are known to cause peripheral leptin resistance (Van Heek et al., 1997Van Heek M. Compton D.S. France C.F. Tedesco R.P. Fawzi A.B. Graziano M.P. Sybertz E.J. Strader C.D. Davis Jr., H.R. Diet-induced obese mice develop peripheral, but not central, resistance to leptin.J. Clin. Invest. 1997; 99: 385-390Crossref PubMed Scopus (650) Google Scholar, El-Haschimi et al., 2000El-Haschimi K. Pierroz D.D. Hileman S.M. Bjorbaek C. Flier J.S. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity.J. Clin. Invest. 2000; 105: 1827-1832Crossref PubMed Scopus (692) Google Scholar), and dietary lipid composition may affect leptin sensitivity. Dietary intake of fish oil appears to influence the regulation of appetite and obesity (Tisdale and Dhesis, 1990Tisdale M.J. Dhesis J.K. Inhibition of weight loss by omega-3 fatty acids in an experimental cachexia model.Cancer Res. 1990; 50: 5022-5026PubMed Google Scholar, Risica et al., 2000aRisica P.M. Schraer C. Ebbesson S.O.E. Nobmann E.D. Caballero B.H. Body fat distribution in Alaskan Eskimos of the Bering Straits region: the Alaskan Siberia Project.Int. J. Obes. Relat. Metab. Disord. 2000; 24: 171-179Crossref PubMed Scopus (28) Google Scholar, Risica et al., 2000bRisica P.M. Schraer C. Ebbesson S.O.E. Nobmann E.D. Caballero B.H. Overweight and obesity among Alaskan Eskimos of the Bering Straits region: the Alaska Siberia Project.Int. J. Obes. Relat. Metab. Disord. 2000; 24: 939-944Crossref PubMed Scopus (29) Google Scholar, Bjerregaard et al., 2002Bjerregaard P. Jorgensen M.E. Andersen S. Mulvad G. Borch-Johnsen K. The Greenland Population Study. Decreasing overweight and central fat patterning with Westernization among the Inuit in Greenland and Inuit migrants.Int. J. Obes. Relat. Metab. Disord. 2002; 26: 1503-1510Crossref PubMed Scopus (30) Google Scholar). Our recent clinical data have demonstrated that serum n-3 polyunsaturated fatty acid (PUFA) concentrations are three times higher in obese subjects than in lean subjects (BMI, 20.5 ± 0.6 kg/m2) 1.36% ± 0.16% (n = 10), obese subjects (BMI, 38.3 ± 1.3 kg/m2); 4.05% ± 0.26% (n = 19) (p < 0.01) (our unpublished data). In addition, Westernization of the diet of Inuit immigrants resulted in a reduction in the proportion of obese people within this population (Bjerregaard et al., 2002Bjerregaard P. Jorgensen M.E. Andersen S. Mulvad G. Borch-Johnsen K. The Greenland Population Study. Decreasing overweight and central fat patterning with Westernization among the Inuit in Greenland and Inuit migrants.Int. J. Obes. Relat. Metab. Disord. 2002; 26: 1503-1510Crossref PubMed Scopus (30) Google Scholar), indicating that fish oil may play a role in the development of human obesity. Leptin is transported to the brain via the arcuate nucleus of the hypothalamus (Banks, 2003Banks W.A. Is obesity a disease of the blood-brain barrier? Physiological, pathological, and evolutional considerations.Curr. Pharm. Des. 2003; 9: 801-809Crossref PubMed Scopus (101) Google Scholar, Schwartz et al., 1996bSchwartz M.W. Seeley R. Campfield L.A. Burn P. Baskin D.G. Identification of targets of leptin action in rat hypothalamus.J. Clin. Invest. 1996; 98: 1101-1106Crossref PubMed Scopus (1348) Google Scholar). While FluoroGold does not penetrate the BBB, it is known to be readily taken up by the arcuate nucleus, even when injected peripherally, suggesting that the arcuate nucleus BBB is poorly developed (Merchenthaler, 1991Merchenthaler I. Neurons with access to the general circulation in the central nervous system of the rat: a retrograde tracing study with fluoro-gold.Neuroscience. 1991; 44: 655-662Crossref PubMed Scopus (126) Google Scholar). Bioactive substances such as leptin can move easily from the general circulation into the neuronal space of the arcuate nucleus as compared to other regions of the hypothalamus. Accumulating evidence suggests that leptin resistance is due to impairment of the transport of leptin from the blood to the brain (Baskin et al., 1998Baskin D.G. Seeley R.J. Kuijper J.L. Lok S. Weigle D.S. Erickson J.C. Palmiter R.D. Schwartz M.W. Increased expression of mRNA for the long form of the leptin receptor in the hypothalamus is associated with leptin hypersensitivity and fasting.Diabetes. 1998; 47: 538-543Crossref PubMed Scopus (148) Google Scholar). Alterations in the way that leptin is transported into the brain via the BBB, along with hypothalamic leptin receptor abnormalities and postreceptor signal transduction mechanisms, are possible contributory factors in the pathogenesis of peripheral leptin resistance in obese patients. Fasting leads to a reduction in the rate of leptin transport through the BBB and into the brain (Kastin and Akerstrom, 2000Kastin A.J. Akerstrom V. Fasting, but not adrenalectomy, reduces transport of leptin into the brain.Peptides. 2000; 21: 679-682Crossref PubMed Scopus (61) Google Scholar), while α1-adrenergic stimulation was shown to enhance the rate of leptin transport into the brain (Banks, 2001Banks W.A. Enhanced leptin transport across the blood-brain barrier by α -adrenergic agents.Brain Res. 2001; 899: 209-217Crossref PubMed Scopus (111) Google Scholar). However, the critical mechanisms involved in the regulation of leptin transport in the hypothalamus are not yet fully understood, even in experimental models of obesity. It was reported that New Zealand Obese (NZO) mice, an animal model of obesity without any obvious genetic defects associated with the leptin receptor, exhibited peripheral leptin resistance, as did rats fed upon a high-fat diet (Takahashi et al., 2001Takahashi H. Oh-Ishi M. Shimizu H. Mori M. Detection and identification of subcutaneous adipose tissue protein related to obesity in New Zealand Obese mouse.Endocr. J. 2001; 48: 205-211Crossref PubMed Scopus (10) Google Scholar). Similar results have also been demonstrated with human obesity. Both mouse and human models associated obesity with reduced uptake of leptin by the brain, while neither of the models exhibited significant reduction in Ob-R expression in isolated cerebral microvessels (Hileman et al., 2002Hileman S.M. Pierroz D.D. Masuzaki H. Bjorbaek C. El-Haschimi K. Banks W. Flier J.S. Characterization of short isoforms of the leptin receptor in rat cerebral microvessels and of brain uptake of leptin in mouse models of obesity.Endocrinology. 2002; 143: 775-783Crossref PubMed Scopus (189) Google Scholar). We have recently found that NZO mice exhibit a reduced ratio of arachidonic acid (AA; n-6) to n-3 PUFA in the sera due to changes associated with lipid metabolism-related enzyme expression in adipose tissue (Takahashi et al., 2001Takahashi H. Oh-Ishi M. Shimizu H. Mori M. Detection and identification of subcutaneous adipose tissue protein related to obesity in New Zealand Obese mouse.Endocr. J. 2001; 48: 205-211Crossref PubMed Scopus (10) Google Scholar). We have also found a similar change in the ratio of AA to n-3 PUFAs in the sera of rats fed upon a high-fat diet (our unpublished data). The majority of the leptin in the arcuate nucleus of the hypothalamus is derived from movement across the BBB and rarely from blood-cerebrospinal fluid traveling via the choroid plexus (Kurrimbux et al., 2004Kurrimbux D. Gaffen Z. Farrell C.L. Martin D. Thomas S.A. The involvement of the blood-brain and the blood-cerebrospinal fluid barriers in the distribution of leptin into and out of the rat brain.Neuroscience. 2004; 123: 527-536Crossref PubMed Scopus (50) Google Scholar). It has been suggested that the receptor-mediated transfer of leptin into the brain appears to occur across the BBB via a saturable system (Banks et al., 1996Banks W.A. Kastin A.J. Huang W. Huang W. Jaspan J.B. Maness L.M. Leptin enters the brain by a saturable system independent of insulin.Peptides. 1996; 2: 305-311Crossref Scopus (1095) Google Scholar). However, the existence of a nonsaturable transport pathway has also been proposed (Rubin and Staddon, 1999Rubin L.L. Staddon J.M. The cell biology of the blood-brain barrier.Annu. Rev. Neurosci. 1999; 22: 11-28Crossref PubMed Scopus (809) Google Scholar). In obesity, the movement of leptin into the rat brain and cerebrospinal fluid is not affected by saturation of the transport carriers. In general, the transport of bioactive substances can be mediated by both transcellular and paracellular mechanisms. Recent studies have revealed that transport through the BBB can be modulated to respond to environmental stimuli (Kastin and Akerstrom, 2000Kastin A.J. Akerstrom V. Fasting, but not adrenalectomy, reduces transport of leptin into the brain.Peptides. 2000; 21: 679-682Crossref PubMed Scopus (61) Google Scholar, Banks, 2001Banks W.A. Enhanced leptin transport across the blood-brain barrier by α -adrenergic agents.Brain Res. 2001; 899: 209-217Crossref PubMed Scopus (111) Google Scholar). Changes of n-3 PUFA composition in brain endothelial cells forming the BBB may affect the ability of leptin to move through the BBB. In the present study, we first demonstrate that n-3 PUFAs cause peripheral leptin resistance in rats resulting in obesity and then investigate a mechanism of peripheral leptin resistance induced by an n-3 PUFA-rich diet. Rats fed a high-fat (56%) diet for 14 days exhibited a significant increase in serum levels of n-3 PUFA (high-fat-fed rats: 3.2% ± 0.4% [wt/wt], n = 8) when compared with rats fed a low-fat diet (2.4% ± 0.2% [wt/wt], n = 8, p < 0.05). This trend was not, however, observed with levels of n-6 PUFA. We examined the influence of fatty acid composition in a diet not containing fish oil upon leptin activity in rats by measuring the effects of intraperitoneal (i.p.) injections of recombinant leptin during the dark phase. Effects were monitored for a period of 3 hr following injection. Injections were made 7 days after rats were first provided with the test diets. Body weight gain over a 7 day period from the first provision of each of the test diet days was significantly higher in rats fed diets containing EPA or DHA than rats fed diets containing other fatty acids (fed non-fish-oil-containing diet, 53.2 ± 1.8 g; stearic acid [18:0]-added diet, 53.1 ± 1.2 g; oleic acid [18:1]-added diet, 52.2 ± 1.1 g; linoleic acid [18:2]-added diet, 53.6 ± 1.4 g; docosahexaenoic acid [DHA; 22:5]-added diet, 60.3 ± 2.6 g [p < 0.05]; eicosapentaenoic acid [EPA; 20:5]-added diet, 62.1 ± 1.5 g [p < 0.01]). As shown in Figure 1, the addition of 0.4% (wt/wt) stearic acid, oleic acid, and linoleic acid did not affect the anorexigenic effects of recombinant leptin on food intake over a period of 3 hr. In contrast, the addition of 0.4% (wt/wt) n-3 PUFA, EPA, and DHA completely deleted the anorexigenic effects of recombinant leptin during this same time period. From these observations, it appears that dietary n-3 PUFAs are involved in the development of insensitivity to peripherally administered recombinant leptin, resulting in significant body weight gain over a 7 day period. In the next experiment, we determined how n-3 PUFAs deleted the anorexigenic effects of recombinant leptin by using EPA. Serum concentration of n-3 PUFA in rats fed a diet containing EPA was three times higher than that seen in rats fed a control diet (non-n-3-PUFA-containing, 3.60% ± 0.91%; n-3-PUFA-containing diet, 10.56% ± 1.61%, p < 0.05, n = 8 each group). As with obese humans, rats fed a diet containing n-3 PUFA exhibited increased levels of n-3 PUFA in their blood. Similar i.p. administration of recombinant leptin (0.5 μg/g body weight) significantly inhibited food intake for 1 hr in animals fed a diet that did not contain fish oil (Figure 2Aa). Significant suppression of feeding for a period of 3 hr was observed in those animals receiving recombinant leptin (5.0 μg/g body weight) administered i.p. (Figure 2Ab). In contrast, i.p. administration of both 0.5 and 5.0 μg/g body weight of recombinant leptin did not show any significant reduction of food intake in animals fed a diet containing 0.4% (wt/wt) n-3 PUFA (EPA) (Figures 2Ba and 2Bb). On the other hand, intracerebroventricular administration of recombinant leptin inhibited food intake in a dose-dependent manner in rats fed a diet containing n-3 PUFA, in a similar manner to control animals fed a diet not containing PUFA (Figure 2C). These data confirmed that n-3 PUFA causes peripheral leptin resistance in rats. Evidence in support of this is that the addition of n-3 PUFA completely deleted the anorexigenic effects of peripherally administered recombinant leptin. Moreover, intracerebroventricular administration of recombinant leptin also inhibited food intake in animals fed a diet not containing fish oil and also a diet supplemented with n-3 PUFA. We next examined whether n-3 PUFA may result in increased body weight due to peripheral leptin resistance and a consequent increase in the proportion of body fat in treated rats (Table 1). The rats fed a diet containing n-3 PUFA gained significantly more body weight over a 2 week period (body weight was measured on day 7 and day 14). Mesenteric white adipose tissue weight was significantly higher in rats fed a diet containing n-3 PUFA for 3 days. At 14 days, subcutaneous, epidydimal, and mesenteric white adipose tissue weight and interscapular brown adipose tissue weight were found to be significantly higher in animals fed a diet containing n-3 PUFA.Table 1Chronological changes of body weight gain, adipose tissue weight, and leptin concentration by n-3 PUFADays/n-3 PUFA3 days/(−)3 days/(+)7 days/(−)7 days/(+)14 days/(−)14 days/(+)ΔBW (mg)36.2 ± 2.543.0 ± 1.252.6 ± 7.167.4 ± 4.4ap < 0.05 versus rats fed non-n-3-PUFA-containing diet.104.3 ± 7.0140.0 ± 7.5bp < 0.005 versus rats fed non-n-3-PUFA-containing diet.Sub (mg)879.2 ± 53.6924.5 ± 45.7887.8 ± 108.91058.4 ± 59.31368.3 ± 97.41786.0 ± 132.6bp < 0.005 versus rats fed non-n-3-PUFA-containing diet.Epi (mg)532.8 ± 41.0584.0 ± 59.9561.4 ± 32.2719.6 ± 39.8bp < 0.005 versus rats fed non-n-3-PUFA-containing diet.1113.7 ± 50.91409.7 ± 62.5bp < 0.005 versus rats fed non-n-3-PUFA-containing diet.Mes (mg)1234.4 ± 57.31580.3 ± 71.8bp < 0.005 versus rats fed non-n-3-PUFA-containing diet.1491.0 ± 87.81918.4 ± 118.2bp < 0.005 versus rats fed non-n-3-PUFA-containing diet.2132.0 ± 115.72661.6 ± 45.3bp < 0.005 versus rats fed non-n-3-PUFA-containing diet.Ret (mg)458.4 ± 26.4452.5 ± 18.5479.8 ± 75.0621.6 ± 49.3987.6 ± 50.51307.6 ± 147.7BAT (mg)288.6 ± 36.0306.5 ± 23.9314.8 ± 25.3377.8 ± 43.0415.3 ± 40.3543.6 ± 20.0bp < 0.005 versus rats fed non-n-3-PUFA-containing diet.S-Leptin (pg/ml)2289.2 ± 309.92174.4 ± 203.72123.8 ± 261.72458.5 ± 342.22182.0 ± 361.22924.0 ± 295.2ap < 0.05 versus rats fed non-n-3-PUFA-containing diet.C-Leptin (pg/ml)192.7 ± 50.3171.0 ± 35.4211.7 ± 39.9146.0 ± 29.2bp < 0.005 versus rats fed non-n-3-PUFA-containing diet.209.6 ± 38.2138.2 ± 31.5bp < 0.005 versus rats fed non-n-3-PUFA-containing diet.ΔBW, body weight gain; Sub, subcutaneous white adipose tissue; Epi, epididymal white adipose tissue; Mes, mesenteric white adipose tissue; Ret, retroperitoneal white adipose tissue; BAT, brown adipose tissue; S-Leptin, serum leptin concentration; C-Leptin, CSF leptin concentration.a p < 0.05 versus rats fed non-n-3-PUFA-containing diet.b p < 0.005 versus rats fed non-n-3-PUFA-containing diet. Open table in a new tab ΔBW, body weight gain; Sub, subcutaneous white adipose tissue; Epi, epididymal white adipose tissue; Mes, mesenteric white adipose tissue; Ret, retroperitoneal white adipose tissue; BAT, brown adipose tissue; S-Leptin, serum leptin concentration; C-Leptin, CSF leptin concentration. We examined changes in the hypothalamic transport of leptin associated with the diet containing n-3 PUFA. Immunoreactive leptin (IRL) concentrations in cerebrospinal fluid (CSF) were significantly higher in rats fed a diet not containing fish oil than in rats fed a diet containing n-3 PUFA without exogenous leptin administration (Figure 2D), thereby indicating that the transport of endogenous leptin may be disturbed by n-3 PUFA. Intraperitoneal administration of recombinant leptin significantly increased CSF-IRL concentration in rats fed a diet not containing fish oil but not in rats fed a diet containing n-3 PUFA. CSF leptin concentration increased to 234 pg/ml in rats fed a diet not containing fish oil compared to 83 pg/ml in rats fed a diet containing n-3 PUFA. As shown in Table 1, n-3 PUFA increased CSF-IRL concentrations over a 2 week period following initial provision of the diet and was also associated with an increase in serum IRL concentration at 14 days. In an effort to measure the transport of exogenously administered leptin across the BBB, we utilized human leptin and observed the transport of this into the CSF by using an ELISA system that selectivity measured human leptin. The concentration human leptin in rat CSF 60 min after the i.p. administration of human leptin was significantly lower in rats fed a diet containing n-3 PUFA than rats fed a diet not containing n-3 PUFA; this was in spite of these groups of animals exhibiting a similar increase in serum human leptin concentration (Figure 2E). The ratio of CSF to serum human leptin was also significantly reduced in rats fed a diet containing n-3 PUFA. These data indicated that the transport of both endogenous and exogenous leptin appears to be disturbed in animals fed diets containing n-3 PUFA. Therefore, n-3 PUFA-rich diets may cause obesity due to the development of peripheral leptin resistance. How does n-3 PUFA manage to disturb the transport of leptin through the BBB into the brain? It is possible that leptin might be transported into the brain by two different pathways: transcellular and paracellular. Possible candidate mechanisms involved in peripheral leptin resistance include changes in leptin binding capacity, leptin transport through the BBB, and postreceptor signal transduction, which may modulate transcellular leptin transport. Ob-Ra is capable of transporting intact leptin across polarized epithelial cells in vitro (Hileman et al., 2000Hileman S.M. Tornoe J. Flier J.S. Bjorbaek C. Transcellular transport of leptin by the short leptin receptor isoforms ObRa in Madin-Darby canine kidney cells.Endocrinology. 2000; 141: 1955-1961Crossref PubMed Scopus (111) Google Scholar). To investigate alterations in the transcellular transport of leptin mediated by the leptin receptor, we evaluated changes in the expression of the hypothalamic leptin receptor (Ob-Ra, short-form; Ob-Rb, long-form) by feeding rats diets containing n-3 PUFA (Figure 3A ). The expression of Ob-Ra and Ob-Rb was unaffected by feeding rats a diet containing n-3 PUFA over a 7 day period. The concentration of the serum soluble leptin receptor (Ob-Re) may also be involved in the development of peripheral leptin resistance (Huang et al., 2001Huang L. Wang Z. Li C. Modulation of circulating leptin levels by its soluble receptors.J. Biol. Chem. 2001; 276: 6343-6349Crossref PubMed Scopus (226) Google Scholar, Zastrow et al., 2003Zastrow O. Seidel B. Kiess W. Thiery J. Keller E. Bottner A. Kratzsch J. The soluble leptin receptor is crucial for leptin action: evidence from clinical and experimental data.Int. J. Obes. Relat. Metab. Disord. 2003; 27: 1472-1478Crossref PubMed Scopus (99) Google Scholar). However, there were no differences in serum concentrations of Ob-Re when compared between rats fed a diet not containing fish oil and those fed a diet supplemented with n-3 PUFA (Figure 3A). These data indicated that the binding capacity of cell membrane-associated leptin and circulating leptin is not changed by diets containing n-3 PUFA and that binding capacities of the leptin receptor are not involved in n-3 PUFA-induced peripheral leptin resistance. There were no obvious differences in the expression of STAT-3, the phosphorylated form of STAT-3 (p-STAT-3), and SOCS-3 prior to the administration of leptin when compared between diets with and" @default.
• W2000221817 created "2016-06-24" @default.
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• W2000221817 date "2005-05-01" @default.
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• W2000221817 title "Molecular mechanisms associated with leptin resistance: n-3 polyunsaturated fatty acids induce alterations in the tight junction of the brain" @default.
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