Leptin is a product of the obese (OB) gene secreted by adipocytes in proportion to fat mass. It decreases food intake and increases energy expenditure by affecting the balance between orexigenic and anorexigenic hypothalamic pathways. Low leptin levels are responsible for the compensatory increase in appetite and body weight and decreased energy expenditure (EE) following caloric deprivation. The anorexia-cachexia syndrome is a complication of many chronic conditions including cancer, chronic obstructive pulmonary disease, congestive heart failure, chronic kidney disease, and aging, where the decrease in body weight and food intake is not followed by a compensatory increase in appetite or decreased EE. Crosstalk between leptin and inflammatory signaling known to be activated in these conditions may be responsible for this paradox. This manuscript will review the evidence and potential mechanisms mediating changes in the leptin pathway in the setting of anorexia and cachexia associated with chronic diseases. 1. Introdiction Leptin was discovered in 1994 by Friedman and colleagues after cloning an obese (OB) gene responsible for obesity in ob/ob mice [1]. It is a 167 amino acid peptide produced by adipocytes and it is a member of the adipocytokine family. Leptin has been noted to play a major role in body mass regulation by acting in the central nervous system to both stimulate energy expenditure and decrease food intake [2–4]. Named after the Greek word leptos, meaning lean, leptin was the first adipocyte-secreted hormone discovered, proving the active role of adipocytes in metabolic signaling. Leptin crosses the blood-brain barrier in a process that is highly regulated [5–8] and its receptors are found both centrally, in the hypothalamus, and peripherally, in pancreatic islets, liver, kidney, lung, skeletal muscle, and bone marrow [9]. Besides its key role on body weight regulation, leptin affects various metabolic pathways, including growth hormone (GH) signaling [10], insulin sensitivity, and lipogenesis [11]. While leptin levels are directly related to adiposity, there are several other factors resulting in individual variability. Leptin secretion is regulated by insulin, glucocorticoids, and catecholamines [3, 12, 13]. Also, females have significantly higher levels of leptin than men, for any degree of fat mass [14]. Along with adiponectin, leptin assists in peripheral insulin sensitization independent of body weight [15–17]. In leptin-deficient (ob/ob) mice, leptin injections led to dose-dependent reductions in serum glucose levels compared to fed
References
[1]
J. L. Halaas, K. S. Gajiwala, M. Maffei et al., “Weight-reducing effects of the plasma protein encoded by the obese gene,” Science, vol. 269, no. 5223, pp. 543–546, 1995.
[2]
J. M. Friedman, “A tale of two hormones,” Nature Medicine, vol. 16, no. 10, pp. 1100–1106, 2010.
[3]
J. M. Friedman, “Modern science versus the stigma of obesity,” Nature Medicine, vol. 10, no. 6, pp. 563–569, 2004.
[4]
J. S. Flier and E. Maratos-Flier, “Lasker lauds leptin,” Cell, vol. 143, no. 1, pp. 9–12, 2010.
[5]
W. A. Banks, “Enhanced leptin transport across the blood-brain barrier by α1-adrenergic agents,” Brain Research, vol. 899, no. 1-2, pp. 209–217, 2001.
[6]
W. A. Banks, “Is obesity a disease of the blood-brain barrier? Physiological, pathological, and evolutionary considerations,” Current Pharmaceutical Design, vol. 9, no. 10, pp. 801–809, 2003.
[7]
W. A. Banks and C. L. Farrell, “Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible,” American Journal of Physiology, vol. 285, no. 1, pp. E10–E15, 2003.
[8]
A. J. Kastin and W. Pan, “Dynamic regulation of leptin entry into brain by the blood-brain barrier,” Regulatory Peptides, vol. 92, no. 1–3, pp. 37–43, 2000.
[9]
S. Margetic, C. Gazzola, G. G. Pegg, and R. A. Hill, “Leptin: a review of its peripheral actions and interactions,” International Journal of Obesity, vol. 26, no. 11, pp. 1407–1433, 2002.
[10]
W. Doehner, C. D. Pflaum, M. Rauchhaus et al., “Leptin, insulin sensitivity and growth hormone binding protein in chronic heart failure with and without cardiac cachexia,” European Journal of Endocrinology, vol. 145, no. 6, pp. 727–735, 2001.
[11]
W. Doehner and S. D. Anker, “Cardiac cachexia in early literature: a review of research prior to Medline,” International Journal of Cardiology, vol. 85, no. 1, pp. 7–14, 2002.
[12]
W. M. Mueller, F. M. Gregoire, K. L. Stanhope et al., “Evidence that glucose metabolism regulates leptin secretion from cultured rat adipocytes,” Endocrinology, vol. 139, no. 2, pp. 551–558, 1998.
[13]
P. Leroy, S. Dessolin, P. Villageois et al., “Expression of ob gene in adipose cells: regulation by insulin,” Journal of Biological Chemistry, vol. 271, no. 5, pp. 2365–2368, 1996.
[14]
C. S. Mantzoros and S. J. Moschos, “Leptin: in search of role(s) in human physiology and pathophysiology,” Clinical Endocrinology, vol. 49, no. 5, pp. 551–567, 1998.
[15]
A. Khan, S. Narangoda, B. Ahren, C. Holm, F. Sundler, and S. Efendic, “Long-term leptin treatment of ob/ob mice improves glucose-induced insulin secretion,” International Journal of Obesity, vol. 25, no. 6, pp. 816–821, 2001.
[16]
C. Koch, R. A. Augustine, J. Steger et al., “Leptin rapidly improves glucose homeostasis in obese mice by increasing hypothalamic insulin sensitivity,” Journal of Neuroscience, vol. 30, no. 48, pp. 16180–16187, 2010.
[17]
J. W. Lee and D. R. Romsos, “Leptin administration normalizes insulin secretion from islets of Lepob/Lepob mice by food intake-dependent and -independent mechanisms,” Experimental Biology and Medicine, vol. 228, no. 2, pp. 183–187, 2003.
[18]
M. W. Schwartz, D. G. Baskin, T. R. Bukowski et al., “Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice,” Diabetes, vol. 45, no. 4, pp. 531–535, 1996.
[19]
M. A. Pelleymounter, M. J. Cullen, M. B. Baker et al., “Effects of the obese gene product on body weight regulation in ob/ob mice,” Science, vol. 269, no. 5223, pp. 540–543, 1995.
[20]
C. T. Montague, I. S. Farooqi, J. P. Whitehead et al., “Congenital leptin deficiency is associated with severe early-onset obesity in humans,” Nature, vol. 387, no. 6636, pp. 903–908, 1997.
[21]
K. Clément, C. Vaisse, N. Lahlou et al., “A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction,” Nature, vol. 392, no. 6674, pp. 398–401, 1998.
[22]
R. V. Considine, M. K. Sinha, M. L. Heiman et al., “Serum immunoreactive-leptin concentrations in normal-weight and obese humans,” New England Journal of Medicine, vol. 334, no. 5, pp. 292–295, 1996.
[23]
B. Burguera, M. E. Couce, G. L. Curran et al., “Obesity is associated with a decreased leptin transport across the blood-brain barrier in rats,” Diabetes, vol. 49, no. 7, pp. 1219–1223, 2000.
[24]
J. F. Caro, J. W. Kolaczynski, M. R. Nyce et al., “Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance,” The Lancet, vol. 348, no. 9021, pp. 159–161, 1996.
[25]
S. P. Kalra, “Circumventing leptin resistance for weight control,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 8, pp. 4279–4281, 2001.
[26]
S. P. Kalra, M. G. Dube, S. Pu, B. Xu, T. L. Horvath, and P. S. Kalra, “Interacting appetite-regulating pathways in the hypothalamic regulation of body weight,” Endocrine Reviews, vol. 20, no. 1, pp. 68–100, 1999.
[27]
M. W. Schwartz, E. Peskind, M. Raskind, E. J. Boyko, and D. Porte Jr., “Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans,” Nature Medicine, vol. 2, no. 5, pp. 589–593, 1996.
[28]
L. A. Campfield, F. J. Smith, Y. Guisez, R. Devos, and P. Burn, “Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks,” Science, vol. 269, no. 5223, pp. 546–549, 1995.
[29]
M. G. Dube, E. Beretta, H. Dhillon, N. Ueno, P. S. Kalra, and S. P. Kalra, “Central leptin gene therapy blocks high-fat diet-induced weight gain, hyperleptinemia, and hyperinsulinemia: increase in serum ghrelin levels,” Diabetes, vol. 51, no. 6, pp. 1729–1736, 2002.
[30]
J. L. Halaas, C. Boozer, J. Blair-West, N. Fidahusein, D. A. Denton, and J. M. Friedman, “Physiological response to long-term peripheral and central leptin infusion in lean and obese mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 16, pp. 8878–8883, 1997.
[31]
P. A. Baldock, A. Sainsbury, S. Allison et al., “Hypothalamic control of bone formation: distinct actions of leptin and Y2 receptor pathways,” Journal of Bone and Mineral Research, vol. 20, no. 10, pp. 1851–1857, 2005.
[32]
H. Dhillon, S. P. Kalra, V. Prima et al., “Central leptin gene therapy suppresses body weight gain, adiposity and serum insulin without affecting food consumption in normal rats: a long-term study,” Regulatory Peptides, vol. 99, no. 2-3, pp. 69–77, 2001.
[33]
A. J. Kastin and V. Akerstrom, “Fasting, but not adrenalectomy, reduces transport of leptin into the brain,” Peptides, vol. 21, no. 5, pp. 679–682, 2000.
[34]
A. J. Kastin and V. Akerstrom, “Glucose and insulin increase the transport of leptin through the blood-brain barrier in normal mice but not in streptozotocin-diabetic mice,” Neuroendocrinology, vol. 73, no. 4, pp. 237–242, 2001.
[35]
K. Chen, F. Li, J. Li et al., “Induction of leptin resistance through direct interaction of C-reactive protein with leptin,” Nature Medicine, vol. 12, no. 4, pp. 425–432, 2006.
[36]
H. Florez, S. Castillo-Florez, A. Mendez et al., “C-reactive protein is elevated in obese patients with the metabolic syndrome,” Diabetes Research and Clinical Practice, vol. 71, no. 1, pp. 92–100, 2006.
[37]
E. Beretta, M. G. Dube, P. S. Kalra, and S. P. Kalra, “Long-term suppression of weight gain, adiposity, and serum insulin by central leptin gene therapy in prepubertal rats: effects on serum ghrelin and appetite-regulating genes,” Pediatric Research, vol. 52, no. 2, pp. 189–198, 2002.
[38]
S. Boghossian, N. Ueno, M. G. Dube, P. Kalra, and S. Kalra, “Leptin gene transfer in the hypothalamus enhances longevity in adult monogenic mutant mice in the absence of circulating leptin,” Neurobiology of Aging, vol. 28, no. 10, pp. 1594–1604, 2007.
[39]
J. P. Bastard, C. Jardel, E. Bruckert et al., “Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss,” Journal of Clinical Endocrinology and Metabolism, vol. 85, no. 9, pp. 3338–3342, 2000.
[40]
I. Wernstedt, B. Olsson, M. Jern？s et al., “Increased levels of acylation-stimulating protein in interleukin-6- deficient (IL-6-/-) mice,” Endocrinology, vol. 147, no. 6, pp. 2690–2695, 2006.
[41]
K. Stenl？f, I. Wernstedt, T. Fj？llman, V. Wallenius, K. Wallenius, and J. O. Jansson, “Interleukin-6 levels in the central nervous system are negatively correlated with fat mass in overweight/obese subjects,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 9, pp. 4379–4383, 2003.
[42]
G. A. Bray and D. A. York, “Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis,” Physiological Reviews, vol. 59, no. 3, pp. 719–809, 1979.
[43]
B. K. Anand and J. R. Brobeck, “Localization of a "feeding center" in the hypothalamus of the rat,” Proceedings of the Society for Experimental Biology and Medicine, vol. 77, no. 2, pp. 323–324, 1951.
[44]
M. A. Cowley, J. L. Smart, M. Rubinstein et al., “Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus,” Nature, vol. 411, no. 6836, pp. 480–484, 2001.
[45]
N. Ibrahim, M. A. Bosch, J. L. Smart et al., “Hypothalamic proopiomelanocortin neurons are glucose responsive and express KATP channels,” Endocrinology, vol. 144, no. 4, pp. 1331–1340, 2003.
[46]
T. L. Horvath, F. Naftolin, S. P. Kalra, and C. Leranth, “Neuropeptide-Y innervation of β-endorphin-containing cells in the rat mediobasal hypothalamus: a light and electron microscopic double immunostaining analysis,” Endocrinology, vol. 131, no. 5, pp. 2461–2467, 1992.
[47]
T. L. Horvath, L. M. Garcia-Segura, and F. Naftolin, “Control of gonadotropin feedback: the possible role of estrogen-induced hypothalamic synaptic plasticity,” Gynecological Endocrinology, vol. 11, no. 2, pp. 139–143, 1997.
[48]
T. L. Horvath, Z. B. Andrews, and S. Diano, “Fuel utilization by hypothalamic neurons: roles for ROS,” Trends in Endocrinology and Metabolism, vol. 20, no. 2, pp. 78–87, 2009.
[49]
S. Diano, “New aspects of melanocortin signaling: a role for PRCP in α-MSH degradation,” Frontiers in Neuroendocrinology, vol. 32, no. 1, pp. 70–83, 2011.
[50]
A. Hinney, A. Schmidt, K. Nottebom et al., “Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans,” Journal of Clinical Endocrinology and Metabolism, vol. 84, no. 4, pp. 1483–1486, 1999.
[51]
C. Vaisse, K. Clement, E. Durand, S. Hercberg, B. Guy-Grand, and P. Froguel, “Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity,” Journal of Clinical Investigation, vol. 106, no. 2, pp. 253–262, 2000.
[52]
A. Sahu, “Minireview: a hypothalamic role in energy balance with special emphasis on leptin,” Endocrinology, vol. 145, no. 6, pp. 2613–2620, 2004.
[53]
S. Pinto, A. G. Roseberry, H. Liu et al., “Rapid rewiring of arcuate nucleus feeding circuits by leptin,” Science, vol. 304, no. 5667, pp. 110–115, 2004.
[54]
Y. Maejima, U. Sedbazar, S. Suyama et al., “Nesfatin-1-regulated oxytocinergic signaling in the paraventricular nucleus causes anorexia through a leptin-independent melanocortin pathway,” Cell Metabolism, vol. 10, no. 5, pp. 355–365, 2009.
[55]
D. Walsh, S. Donnelly, and L. Rybicki, “The symptoms of advanced cancer: relationship to age, gender, and performance status in 1,000 patients,” Supportive Care in Cancer, vol. 8, no. 3, pp. 175–179, 2000.
[56]
W. D. Dewys, C. Begg, P. T. Lavin, et al., “Prognostic effect of weight loss prior to chemotherapy in cancer patients,” American Journal of Medicine, vol. 69, no. 4, pp. 491–497, 1980.
[57]
P. O'Gorman, D. C. McMillan, and C. S. McArdle, “Impact of weight loss, appetite, and the inflammatory response on quality of life in gastrointestinal cancer patients,” Nutrition and Cancer, vol. 32, no. 2, pp. 76–80, 1998.
[58]
M. J. Tisdale, “Cachexia in cancer patients,” Nature Reviews Cancer, vol. 2, no. 11, pp. 862–871, 2002.
[59]
C. R. Plata-Salamán, “Cytokines and feeding,” International Journal of Obesity, vol. 25, supplement 5, pp. S48–S52, 2001.
[60]
A. Laviano, M. M. Meguid, and F. Rossi-Fanelli, “Cancer anorexia: clinical implications, pathogenesis, and therapeutic strategies,” The Lancet Oncology, vol. 4, no. 11, pp. 686–694, 2003.
[61]
M. E. Martignoni, P. Kunze, and H. Friess, “Cancer cachexia,” Molecular Cancer, vol. 2, article 36, 2003.
[62]
S. R. Broussard, R. H. Mccusker, J. E. Novakofski et al., “Cytokine-hormone interactions: tumor necrosis factor α impairs biologic activity and downstream activation signals of the insulin-like growth factor I receptor in myoblasts,” Endocrinology, vol. 144, no. 7, pp. 2988–2996, 2003.
[63]
R. A. Frost and C. H. Lang, “Alteration of somatotropic function by proinflammatory cytokines,” Journal of Animal Science, vol. 82, pp. E100–E109, 2004.
[64]
G. H. Lee, R. Proenca, J. M. Montez et al., “Abnormal splicing of the leptin receptor in diabetic mice,” Nature, vol. 379, no. 6566, pp. 632–635, 1996.
[65]
M. W. Schwartz and G. J. Morton, “Keeping hunger at bay,” Nature, vol. 418, no. 6898, pp. 595–597, 2002.
[66]
C. Grunfeld, C. Zhao, J. Fuller et al., “Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters,” Journal of Clinical Investigation, vol. 97, no. 9, pp. 2152–2157, 1996.
[67]
B. E. Wisse, K. Ogimoto, G. J. Morton et al., “Physiological regulation of hypothalamic IL-1β gene expression by leptin and glucocorticoids: implications for energy homeostasis,” American Journal of Physiology, vol. 287, no. 6, pp. E1107–E1113, 2004.
[68]
G. N. Luheshi, J. D. Gardner, D. A. Rushforth, A. S. Loudon, and N. J. Rothwell, “Leptin actions on food intake and body temperature are mediated by IL-1,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 12, pp. 7047–7052, 1999.
[69]
V. Sergeyev, C. Broberger, and T. H？kfelt, “Effect of LPS administration on the expression of POMC, NPY, galanin, CART and MCH mRNAs in the rat hypothalamus,” Molecular Brain Research, vol. 90, no. 2, pp. 93–100, 2001.
[70]
D. L. Marks, N. Ling, and R. D. Cone, “Role of the central melanocortin system in cachexia,” Cancer Research, vol. 61, no. 4, pp. 1432–1438, 2001.
[71]
G. Mantovani, A. Macciò, L. Mura et al., “Serum levels of leptin and proinflammatory cytokines in patients with advanced-stage cancer at different sites,” Journal of Molecular Medicine, vol. 78, no. 10, pp. 554–561, 2000.
[72]
H. Baumann and J. Gauldie, “The acute phase response,” Immunology Today, vol. 15, no. 2, pp. 74–80, 1994.
[73]
A. Laviano, M. M. Meguid, Z. J. Yang, J. R. Gleason, C. Cangiano, and F. R. Fanelli, “Cracking the riddle of cancer anorexia,” Nutrition, vol. 12, no. 10, pp. 706–710, 1996.
[74]
P. G. Jang, C. Namkoong, G. M. Kang et al., “NF-κB activation in hypothalamic pro-opiomelanocortin neurons is essential in illness- and leptin-induced anorexia,” Journal of Biological Chemistry, vol. 285, no. 13, pp. 9706–9715, 2010.
[75]
J. P. Thaler, S. J. Choi, M. W. Schwartz, and B. E. Wisse, “Hypothalamic inflammation and energy homeostasis: resolving the paradox,” Frontiers in Neuroendocrinology, vol. 31, no. 1, pp. 79–84, 2010.
[76]
V. Mohamed-Ali, S. Goodrick, A. Rawesh et al., “Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-α, in vivo,” Journal of Clinical Endocrinology and Metabolism, vol. 82, no. 12, pp. 4196–4200, 1997.
[77]
F. Kim, M. Pham, E. Maloney et al., “Vascular inflammation, insulin resistance, and reduced nitric oxide production precede the onset of peripheral insulin resistance,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 11, pp. 1982–1988, 2008.
[78]
C. T. De Souza, E. P. Araujo, S. Bordin et al., “Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus,” Endocrinology, vol. 146, no. 10, pp. 4192–4199, 2005.
[79]
K. A. Posey, D. J. Clegg, R. L. Printz et al., “Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet,” American Journal of Physiology, vol. 296, no. 5, pp. E1003–E1012, 2009.
[80]
X. Zhang, G. Zhang, H. Zhang, M. Karin, H. Bai, and D. Cai, “Hypothalamic IKKβ/NF-κB and ER stress link overnutrition to energy imbalance and obesity,” Cell, vol. 135, no. 1, pp. 61–73, 2008.
[81]
L. Ozcan, A. S. Ergin, A. Lu et al., “Endoplasmic reticulum stress plays a central role in development of leptin resistance,” Cell Metabolism, vol. 9, no. 1, pp. 35–51, 2009.
[82]
M. Milanski, G. Degasperi, A. Coope et al., “Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity,” Journal of Neuroscience, vol. 29, no. 2, pp. 359–370, 2009.
[83]
M. Burstow, T. Kelly, S. Panchani et al., “Outcome of palliative esophageal stenting for malignant dysphagia: a retrospective analysis,” Diseases of the Esophagus, vol. 22, no. 6, pp. 519–525, 2009.
[84]
H. Suzuki, H. Hashimoto, M. Kawasaki et al., “Similar changes of hypothalamic feeding-regulating peptides mRNAs and plasma leptin levels in PTHrP-, LIF-secreting tumors-induced cachectic rats and adjuvant arthritic rats,” International Journal of Cancer, vol. 128, no. 9, pp. 2215–2223, 2011.
[85]
Q. Ding, T. Mracek, P. Gonzalez-Muniesa et al., “Identification of macrophage inhibitory cytokine-1 in adipose tissue and its secretion as an adipokine by human adipocytes,” Endocrinology, vol. 150, no. 4, pp. 1688–1696, 2009.
[86]
B. Weryńska, M. Kosacka, M. Go？ecki, and R. Jankowska, “Leptin serum levels in cachectic and non-cachectic lung cancer patients,” Pneumonologia i Alergologia Polska, vol. 77, no. 6, pp. 500–506, 2009.
[87]
J. Smiechowska, A. Utech, G. Taffet, T. Hayes, M. Marcelli, and J. M. Garcia, “Adipokines in patients with cancer anorexia and cachexia,” Journal of Investigative Medicine, vol. 58, no. 3, pp. 554–559, 2010.
[88]
C. Bing, S. Taylor, M. J. Tisdale, and G. Williams, “Cachexia in MAC16 adenocarcinoma: suppression of hunger despite normal regulation of leptin, insulin and hypothalamic neuropeptide Y,” Journal of Neurochemistry, vol. 79, no. 5, pp. 1004–1012, 2001.
[89]
A. Macciò, C. Madeddu, D. Massa et al., “Interleukin-6 and leptin as markers of energy metabolicchanges in advanced ovarian cancer patients,” Journal of Cellular and Molecular Medicine, vol. 13, no. 9, pp. 3951–3959, 2009.
[90]
P. Costelli, N. Carbo, L. Tessitore et al., “Tumor necrosis factor-α mediates changes in tissue protein turnover in a rat cancer cachexia model,” Journal of Clinical Investigation, vol. 92, no. 6, pp. 2783–2789, 1993.
[91]
R. M. Goldberg, C. L. Loprinzi, J. A. Mailliard et al., “Pentoxifylline for treatment of cancer anorexia and cachexia? A randomized, double-blind, placebo-controlled trial,” Journal of Clinical Oncology, vol. 13, no. 11, pp. 2856–2859, 1995.
[92]
E. Bruera, C. M. Neumann, E. Pituskin, K. Calder, G. Ball, and J. Hanson, “Thalidomide in patients with cachexia due to terminal cancer: preliminary report,” Annals of Oncology, vol. 10, no. 7, pp. 857–859, 1999.
[93]
K. Mori, K. Fujimoto-Ouchi, T. Ishikawa, F. Sekiguchi, H. Ishitsuka, and Y. Tanaka, “Murine interleukin-12 prevents the development of cancer cachexia in a murine model,” International Journal of Cancer, vol. 67, no. 6, pp. 849–855, 1996.
[94]
N. Carbó, J. López-Soriano, P. Costelli et al., “Interleukin-15 antagonizes muscle protein waste in tumour-bearing rats,” British Journal of Cancer, vol. 83, no. 4, pp. 526–531, 2000.
[95]
G. Mantovani, A. MacCiò, C. Madeddu et al., “Phase II nonrandomized study of the efficacy and safety of COX-2 inhibitor celecoxib on patients with cancer cachexia,” Journal of Molecular Medicine, vol. 88, no. 1, pp. 85–92, 2010.
[96]
S. D. Anker, A. Negassa, A. J. S. Coats et al., “Prognostic importance of weight loss in chronic heart failure and the effect of treatment with angiotensin-converting-enzyme inhibitors: an observational study,” The Lancet, vol. 361, no. 9363, pp. 1077–1083, 2003.
[97]
S. D. Anker, P. Ponikowski, S. Varney et al., “Wasting as independent risk factor for mortality in chronic heart failure,” The Lancet, vol. 349, no. 9058, pp. 1050–1053, 1997.
[98]
C. R. Gibbs, G. Jackson, and G. Y. H. Lip, “ABC of heart failure: non-drug management,” British Medical Journal, vol. 320, no. 7231, pp. 366–369, 2000.
[99]
B. Levine, J. Kalman, L. Mayer, H. M. Fillit, and M. Packer, “Elevated circulating levels of tumor necrosis factor in severe chronic heart failure,” New England Journal of Medicine, vol. 323, no. 4, pp. 236–241, 1990.
[100]
G. S. Filippatos, K. Tsilias, K. Venetsanou et al., “Leptin serum levels in cachectic heart failure patient. Relationship with tumor necrosis factor-α system,” International Journal of Cardiology, vol. 76, no. 2-3, pp. 117–122, 2000.
[101]
D. R. Murdoch, E. Rooney, H. J. Dargie, D. Shapiro, J. J. Morton, and J. J. V. McMurray, “Inappropriately low plasma leptin concentration in the cachexia associated with chronic heart failure,” Heart, vol. 82, no. 3, pp. 352–356, 1999.
[102]
M. J. Toth, S. S. Gottlieb, M. L. Fisher, A. S. Ryan, B. J. Nicklas, and E. T. Poehlman, “Plasma leptin concentrations and energy expenditure in heart failure patients,” Metabolism, vol. 46, no. 4, pp. 450–453, 1997.
[103]
G. Paolisso, M. R. Rizzo, G. Mazziotti et al., “Lack of association between changes in plasma leptin concentration and in food intake during the menstrual cycle,” European Journal of Clinical Investigation, vol. 29, no. 6, pp. 490–495, 1999.
[104]
M. W. Nickola, L. E. Wold, P. B. Colligan, G. J. Wang, W. K. Samson, and J. Ren, “Leptin attenuates cardiac contraction in rat ventricular myocytes role of NO,” Hypertension, vol. 36, no. 4, pp. 501–505, 2000.
[105]
K. R. McGaffin, C. S. Moravec, and C. F. McTiernan, “Leptin signaling in the failing and mechanically unloaded human heart,” Circulation, vol. 2, no. 6, pp. 676–683, 2009.
[106]
P. C. Schulze, J. Kratzsch, A. Linke et al., “Elevated serum levels of leptin and soluble leptin receptor in patients with advanced chronic heart failure,” European Journal of Heart Failure, vol. 5, no. 1, pp. 33–40, 2003.
[107]
F. Leyva, S. D. Anker, K. Egerer, J. C. Stevenson, W. J. Kox, and A. J. S. Coats, “Hyperleptinaemia in chronic heart failure. Relationships with insulin,” European Heart Journal, vol. 19, no. 10, pp. 1547–1551, 1998.
[108]
T. Tsutamoto, T. Hisanaga, A. Wada et al., “Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure,” Journal of the American College of Cardiology, vol. 31, no. 2, pp. 391–398, 1998.
[109]
V. Sharma and J. H. McNeill, “The emerging roles of leptin and ghrelin in cardiovascular physiology and pathophysiology,” Current Vascular Pharmacology, vol. 3, no. 2, pp. 169–180, 2005.
[110]
W. G. Haynes, W. I. Sivitz, D. A. Morgan, S. A. Walsh, and A. L. Mark, “Sympathetic and cardiorenal actions of leptin,” Hypertension, vol. 30, no. 3, pp. 619–623, 1997.
[111]
W. G. Haynes, D. A. Morgan, S. A. Walsh, W. I. Sivitz, and A. L. Mark, “Cardiovascular consequences of obesity: role of leptin,” Clinical and Experimental Pharmacology and Physiology, vol. 25, no. 1, pp. 65–69, 1998.
[112]
G. Lembo, C. Vecchione, L. Fratta et al., “Leptin induces direct vasodilation through distinct endothelial mechanisms,” Diabetes, vol. 49, no. 2, pp. 293–297, 2000.
[113]
S. D. Anker and S. Von Haehling, “Inflammatory mediators in chronic heart failure: an overview,” Heart, vol. 90, no. 4, pp. 464–470, 2004.
[114]
R. Ferrari, T. Bachetti, R. Confortini et al., “Tumor necrosis factor soluble receptors in patients with various degrees of congestive heart failure,” Circulation, vol. 92, no. 6, pp. 1479–1486, 1995.
[115]
M. Rauchhaus, W. Doehner, D. P. Francis et al., “Plasma cytokine parameters and mortality in patients with chronic heart failure,” Circulation, vol. 102, no. 25, pp. 3060–3067, 2000.
[116]
T. G. Kirchgessner, K. T. Uysal, S. M. Wiesbrock, M. W. Marino, and G. S. Hotamisligil, “Tumor necrosis factor-α contributes to obesity-related hyperleptinemia by regulating leptin release from adipocytes,” Journal of Clinical Investigation, vol. 100, no. 11, pp. 2777–2782, 1997.
[117]
D. Kova？i？, M. Marin？ek, L. Gobec, M. Lain？？ak, and M. Podbregar, “Effect of selective and non-selective β-blockers on body weight, insulin resistance and leptin concentration in chronic heart failure,” Clinical Research in Cardiology, vol. 97, no. 1, pp. 24–31, 2008.
[118]
Y. Schutz and V. Woringer, “Obesity in switzerland: a critical assessment of prevalence in children and adults,” International Journal of Obesity, vol. 26, supplement 2, pp. S3–S11, 2002.
[119]
M. K. Sridhar, R. Carter, M. E. J. Lean, and S. W. Banham, “Resting energy expenditure and nutritional state of patients with increased oxygen cost of breathing due to emphysema, scoliosis and thoracoplasty,” Thorax, vol. 49, no. 8, pp. 781–785, 1994.
[120]
O. Hugli, Y. Schutz, and J. W. Fitting, “The cost of breathing in stable chronic obstructive pulmonary disease,” Clinical Science, vol. 89, no. 6, pp. 625–632, 1995.
[121]
M. Di Francia, D. Barbier, J. L. Mege, and J. Orehek, “Tumor necrosis factor-alpha levels and weight loss in chronic obstructive pulmonary disease,” American Journal of Respiratory and Critical Care Medicine, vol. 150, no. 5, pp. 1453–1455, 1994.
[122]
I. De Godoy, M. Donahoe, W. J. Calhoun, J. Mancino, and R. M. Rogers, “Elevated TNF-α production by peripheral blood monocytes of weight-losing COPD patients,” American Journal of Respiratory and Critical Care Medicine, vol. 153, no. 2, pp. 633–637, 1996.
[123]
P. Sarraf, R. C. Frederich, E. M. Turner et al., “Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia,” Journal of Experimental Medicine, vol. 185, no. 1, pp. 171–175, 1997.
[124]
M. S. Zumbach, M. W. J. Boehme, P. Wahl, W. Stremmel, R. Ziegler, and P. P. Nawroth, “Tumor necrosis factor increases serum leptin levels in humans,” Journal of Clinical Endocrinology and Metabolism, vol. 82, no. 12, pp. 4080–4082, 1997.
[125]
N. Takabatake, H. Nakamura, S. Abe et al., “Circulating leptin in patients with chronic obstructive pulmonary disease,” American Journal of Respiratory and Critical Care Medicine, vol. 159, no. 4, pp. 1215–1219, 1999.
[126]
N. Takabatake, H. Nakamura, O. Minamihaba et al., “A novel pathophysiologic phenomenon in cachexic patients with chronic obstructive pulmonary disease: the relationship between the circadian rhythm of circulating leptin and the very low-frequency component of heart rate variability,” American Journal of Respiratory and Critical Care Medicine, vol. 163, no. 6, pp. 1314–1319, 2001.
[127]
C. P. O'Donnell, C. D. Schaub, A. S. Haines et al., “Leptin prevents respiratory depression in obesity,” American Journal of Respiratory and Critical Care Medicine, vol. 159, no. 5, pp. 1477–1484, 1999.
[128]
C. G. Tankersley, C. O'Donnell, M. J. Daood et al., “Leptin attenuates respiratory complications associated with the obese phenotype,” Journal of Applied Physiology, vol. 85, no. 6, pp. 2261–2269, 1998.
[129]
H. Groeben, S. Meier, R. H. Brown, C. P. O'Donnell, W. Mitzner, and C. G. Tankersley, “The effect of leptin on the ventilatory response to hyperoxia,” Experimental Lung Research, vol. 30, no. 7, pp. 559–570, 2004.
[130]
C. Tankersley, S. Kleeberger, B. Russ, A. Schwartz, and P. Smith, “Modified control of breathing in genetically obese (ob/ob) mice,” Journal of Applied Physiology, vol. 81, no. 2, pp. 716–723, 1996.
[131]
A. Grosfeld, J. André, S. H.-D. Mouzon, E. Berra, J. Pouysségur, and M. Guerre-Millo, “Hypoxia-inducible factor 1 transactivates the human leptin gene promoter,” Journal of Biological Chemistry, vol. 277, no. 45, pp. 42953–42957, 2002.
[132]
S. Budweiser, F. Heinemann, K. Meyer, P. J. Wild, and M. Pfeifer, “Weight gain in cachectic COPD patients receiving noninvasive positive-pressure ventilation,” Respiratory Care, vol. 51, no. 2, pp. 126–132, 2006.
[133]
K. J. Tracey, “The inflammatory reflex,” Nature, vol. 420, no. 6917, pp. 853–859, 2002.
[134]
R. H. Mak, W. Cheung, R. D. Cone, and D. L. Marks, “Leptin and inflammation-associated cachexia in chronic kidney disease,” Kidney International, vol. 69, no. 5, pp. 794–797, 2006.
[135]
W. W. Cheung, K. H. Paik, and R. H. Mak, “Inflammation and cachexia in chronic kidney disease,” Pediatric Nephrology, vol. 25, no. 4, pp. 711–724, 2010.
[136]
A. Scholze, D. Rattensperger, W. Zidek, and M. Tepel, “Low serum leptin predicts mortality in patients with chronic kidney disease stage 5,” Obesity, vol. 15, no. 6, pp. 1617–1622, 2007.
[137]
I. Beberashvili, I. Sinuani, A. Azar et al., “Longitudinal study of leptin levels in chronic hemodialysis patients,” Nutrition Journal, vol. 10, article 68, no. 1, 2011.
[138]
P. Stenvinkel, “Leptin—a new hormone of definite interest for the nephrologist,” Nephrology Dialysis Transplantation, vol. 13, no. 5, pp. 1099–1101, 1998.
[139]
A. Aguilera, J. A. Sánchez-Tomero, and R. Selgas, “Brain activation in uremic anorexia,” Journal of Renal Nutrition, vol. 17, no. 1, pp. 57–61, 2007.
[140]
A. F. Suffredini, G. Fantuzzi, R. Badolato, J. J. Oppenheim, and N. P. O'Grady, “New insights into the biology of the acute phase response,” Journal of Clinical Immunology, vol. 19, no. 4, pp. 203–214, 1999.
[141]
R. Pecoits-Filho, L. C. Sylvestre, and P. Stenvinkel, “Chronic kidney disease and inflammation in pediatric patients: from bench to playground,” Pediatric Nephrology, vol. 20, no. 6, pp. 714–720, 2005.
[142]
K. Kalantar-Zadeh, P. Stenvinkel, L. Pillon, and J. D. Kopple, “Inflammation and nutrition in renal insufficiency,” Advances in Renal Replacement Therapy, vol. 10, no. 3, pp. 155–169, 2003.
[143]
R. H. Mak and W. Cheung, “Energy homeostasis and cachexia in chronic kidney disease,” Pediatric Nephrology, vol. 21, no. 12, pp. 1807–1814, 2006.
[144]
R. H. Mak and W. Cheung, “Adipokines and gut hormones in end-stage renal disease,” Peritoneal Dialysis International, vol. 27, supplement 2, pp. S298–S302, 2007.
[145]
W. Cheung, P. X. Yu, B. M. Little, R. D. Cone, D. L. Marks, and R. H. Mak, “Role of leptin and melanocortin signaling in uremia-associated cachexia,” Journal of Clinical Investigation, vol. 115, no. 6, pp. 1659–1665, 2005.
[146]
P. J. Scarpace, M. Matheny, R. L. Moore, and N. Tümer, “Impaired leptin responsiveness in aged rats,” Diabetes, vol. 49, no. 3, pp. 431–435, 2000.
[147]
T. Wolden-Hanson, “Mechanisms of the anorexia of aging in the Brown Norway rat,” Physiology and Behavior, vol. 88, no. 3, pp. 267–276, 2006.
[148]
E. W. Shek and P. J. Scarpace, “Resistance to the anorexic and thermogenic effects of centrally administrated leptin in obese aged rats,” Regulatory Peptides, vol. 92, no. 1–3, pp. 65–71, 2000.
[149]
D. A. Gruenewald, M. A. Naai, B. T. Marck, and A. M. Matsumoto, “Age-related decrease in neuropeptide-Y gene expression in the arcuate nucleus of the male rat brain is independent of testicular feedback,” Endocrinology, vol. 134, no. 6, pp. 2383–2389, 1994.
[150]
D. Horrillo, J. Sierra, C. Arribas et al., “Age-associated development of inflammation in Wistar rats: effects of caloric restriction,” Archives of Physiology and Biochemistry, vol. 117, no. 3, pp. 140–150, 2011.
[151]
J. J. Carrero, A. Nakashima, A. R. Qureshi et al., “Protein-energy wasting modifies the association of ghrelin with inflammation, leptin, and mortality in hemodialysis patients,” Kidney International, vol. 79, no. 7, pp. 749–756, 2011.
[152]
A. van Tellingen, M. P. C. Grooteman, M. Schoorl et al., “Enhanced long-term reduction of plasma leptin concentrations by super-flux polysulfone dialysers,” Nephrology Dialysis Transplantation, vol. 19, no. 5, pp. 1198–1203, 2004.
[153]
E. D. Javor, E. K. Cochran, C. Musso, J. R. Young, A. M. DePaoli, and P. Gorden, “Long-term efficacy of leptin replacement in patients with generalized lipodystrophy,” Diabetes, vol. 54, no. 7, pp. 1994–2002, 2005.
[154]
A. B. Newman, D. Yanez, T. Harris, A. Duxbury, P. L. Enright, and L. P. Fried, “Weight change in old age and its association with mortality,” Journal of the American Geriatrics Society, vol. 49, no. 10, pp. 1309–1318, 2001.
[155]
G. Hauser and M. Neumann, “Aging with quality of life—a challenge for society,” Journal of Physiology and Pharmacology, vol. 56, supplement 2, pp. 35–48, 2005.
[156]
Z. Kmiec, “Central regulation of food intake in ageing,” Journal of Physiology and Pharmacology, vol. 57, supplement 6, pp. 7–16, 2006.
[157]
C. Fernández-Galaz, T. Fernández-Agulló, F. Campoy et al., “Decreased leptin uptake in hypothalamic nuclei with ageing in Wistar rats,” Journal of Endocrinology, vol. 171, no. 1, pp. 23–32, 2001.
[158]
D. A. Gruenewald, B. T. Marck, and A. M. Matsumoto, “Fasting-induced increases in food intake and neuropeptide Y gene expression are attenuated in aging male brown Norway rats,” Endocrinology, vol. 137, no. 10, pp. 4460–4467, 1996.
[159]
T. Wolden-Hanson, B. T. Marck, and A. M. Matsumoto, “Blunted hypothalamic neuropeptide gene expression in response to fasting, but preservation of feeding responses to AgRP in aging male Brown Norway rats,” American Journal of Physiology, vol. 287, no. 1, pp. R138–R146, 2004.
[160]
O. Bouillanne, C. Dupont-Belmont, P. Hay, B. Hamon-Vilcot, L. Cynober, and C. Aussel, “Fat mass protects hospitalized elderly persons against morbidity and mortality,” American Journal of Clinical Nutrition, vol. 90, no. 3, pp. 505–510, 2009.
[161]
Y. Arai, M. Takayama, Y. Abe, and N. Hirose, “Adipokines and aging,” Journal of Atherosclerosis and Thrombosis, vol. 18, no. 7, pp. 545–550, 2011.
[162]
M. Zamboni, E. Zoico, F. Fantin et al., “Relation between leptin and the metabolic syndrome in elderly women,” Journals of Gerontology, vol. 59, no. 4, pp. 396–400, 2004.
[163]
P. J. Enriori, A. E. Evans, P. Sinnayah et al., “Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons,” Cell Metabolism, vol. 5, no. 3, pp. 181–194, 2007.
[164]
R. E. Hubbard, M. S. O, B. L. Calver, and K. W. Woodhouse, “Nutrition, inflammation, and leptin levels in aging and frailty,” Journal of the American Geriatrics Society, vol. 56, no. 2, pp. 279–284, 2008.
