렙틴 저항성의 개선
Improvement of Leptin Resistance
1
조회
0
다운로드
2
인용
0
참고문헌
키워드
초록
Leptin, a 16-kDa cytokine, is secreted by adipose tissue in response to the surplus of fat store. Thereby, the brain is informed about the body's energy status. In the hypothalamus, leptin triggers specific neuronal subpopulations (e.g., POMC and NPY neurons) and activates several intracellular signaling events, including the JAK/STAT, MAPK, PI3K, and mTOR pathway, which eventually translates into decreased food intake and increased energy expenditure. Leptin signal is inhibited by a feedback inhibitory pathway mediated by SOCS3. PTP1B involves another inhibitory pathway of leptin. Leptin potently promotes fat mass loss and body weight reduction in lean subjects. However, it is not widely used in the clinical field because of leptin resistance, which is a common feature of obesity characterized by hyperleptinemia and the failure of exogenous leptin administration to provide therapeutic benefit in rodents and humans. The potential mechanisms of leptin resistance include the following: 1) increases in circulating leptin-binding proteins, 2) reduced transport of leptin across the blood-brain barrier, 3) decreased leptin receptor-B (LRB), and/or 4) the provocation of processes that diminish cellular leptin signaling (inflammation, endoplasmic reticulum stress, feedback inhibition, etc.). Thus, interference of the cellular mechanisms that attenuate leptin signaling improves leptin action in cells and animal models, suggesting the potential utility of these processes as points of therapeutic intervention. Various experimental trials and compounds that improve leptin resistance are introduced in this paper.
Abstract
Leptin, a 16-kDa cytokine, is secreted by adipose tissue in response to the surplus of fat store. Thereby, the brain is informed about the body's energy status. In the hypothalamus, leptin triggers specific neuronal subpopulations (e.g., POMC and NPY neurons) and activates several intracellular signaling events, including the JAK/STAT, MAPK, PI3K, and mTOR pathway, which eventually translates into decreased food intake and increased energy expenditure. Leptin signal is inhibited by a feedback inhibitory pathway mediated by SOCS3. PTP1B involves another inhibitory pathway of leptin. Leptin potently promotes fat mass loss and body weight reduction in lean subjects. However, it is not widely used in the clinical field because of leptin resistance, which is a common feature of obesity characterized by hyperleptinemia and the failure of exogenous leptin administration to provide therapeutic benefit in rodents and humans. The potential mechanisms of leptin resistance include the following: 1) increases in circulating leptin-binding proteins, 2) reduced transport of leptin across the blood-brain barrier, 3) decreased leptin receptor-B (LRB), and/or 4) the provocation of processes that diminish cellular leptin signaling (inflammation, endoplasmic reticulum stress, feedback inhibition, etc.). Thus, interference of the cellular mechanisms that attenuate leptin signaling improves leptin action in cells and animal models, suggesting the potential utility of these processes as points of therapeutic intervention. Various experimental trials and compounds that improve leptin resistance are introduced in this paper.
참고문헌 (52)
- Halaas JL, "Physiological response to long-term peripheral and central leptin infusion in lean and obese mice", Proc Natl Acad Sci USA, 94, pp.8878~8883 (1997)
- Zhang Y, "Positional cloning of the mouse obese gene and its human homologue", Nature, 372, pp.425~432 (1994)
- Schwartz MW, "Central nervous system control of food intake", Nature, 404, pp.661~671 (2000)
- Flier JS, "Obesity wars: molecular progress confronts an expanding epidemic", Cell, 116, pp.337~350 (2004)
- Harrold JA, "Hypothalamic control of energy balance", Curr Drug Targets, 5, pp.207~219 (2004)
- Banks WA, "Impaired transport of leptin across the blood-brain barrier in obesity", Peptides, 20, pp.1341~1345 (1999)
- Kim YW, "Metformin restores leptin sensitivity in high-fat-fed obese rats with leptin resistance", Diabetes, 55, pp.716~724 (2006)
- El-Haschimi K, "Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity", J Clin Invest, 105, pp.1827~1832 (2000)
- Banks WA, "Triglycerides induce leptin resistance at the blood-brain barrier", Diabetes, 53, pp.1253~1260 (2004)
- Oh-I S, "Molecular mechanisms associated with leptin resistance: n-3polyunsaturated fatty acids induce alterations in the tight junction of the brain", Cell Metab, 1, pp.331~341 (2005)
- Dietrich MO, "Megalin mediates the transport of leptin across the blood-CSF barrier", Neurobiol Aging, 29, pp.902~912 (2008)
- Banks WA, "Principles of strategic drug delivery to the brain (SDDB): development of anorectic and orexigenic analogs of leptin", Physiol Behav, 105, pp.145~149 (2011)
- Schulz C, "Intranasal leptin reduces appetite and induces weight loss in rats with diet-induced obesity (DIO)", Endocrinology, 153, pp.143~153 (2012)
- Hileman SM, "Characterizaton of short isoforms of the leptin receptor in rat cerebral microvessels and of brain uptake of leptin in mouse models of obesity", Endocrinology, 143, pp.775~783 (2002)
- Sahu A, "Nutritional regulation of hypothalamic leptin receptor gene expression is defective in diet-induced obesity", J Neuroendocrinol, 14, pp.887~893 (2002)
- Baskin DG, "Increased expression of mRNA for the long form of the leptin receptor in the hypothalamus is associated with leptin hypersensitivity and fasting", Diabetes, 47, pp.538~543 (1998)
- 박성철, "반복적인 금식으로 인한 렙틴 농도 변동이 렙틴 감수성에 미치는 영향", Endocrinology and Metabolism, 23(5), pp.310~318 (2008), 대한내분비학회
- Peiser C, "Leptin receptor expression and suppressor of cytokine signaling transcript levels in highfat-fed rats", Life Sci, 67, pp.2971~2981 (2000)
- Carvalheira JB, "Insulin modulates leptin-induced STAT3activation in rat hypothalamus", FEBS Lett, 500, pp.119~124 (2001)
- Daniel JA, "Effect of cerebroventricular infusion of insulin and (or) glucose on hypothalamic expression of leptin receptor and pituitary secretion of LH in diet-restricted ewes", Domest Anim Endocrinol, 18, pp.177~185 (2000)
- Tortoriello DV, "Increased expression of hypothalamic leptin receptor and adiponectin accompany resistance to dietary-induced obesity and infertility in female C57BL", 6J mice, 2007, pp.31, 395~402
- Keen-Rhinehart E, "AAV-mediated leptin receptor installation improves energy balance and the reproductive status of obese female Koletsky rats", Peptides, 26, pp.2567~2578 (2005)
- Gamber KM, "Over-expression of leptin receptors in hypothalamic POMC neurons increases susceptibility to diet-induced obesity", PLoS One, 7, pp.e30485~ (2012)
- Martin TL, "Diet-induced obesity alters AMP kinase activity in hypothalamus and skeletal muscle", J Biol Chem, 281, pp.18933~18941 (2006)
- Howard JK, "Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3", Nat Med, 10, pp.734~738 (2004)
- Björnholm M, "Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function", J Clin Invest, 117, pp.1354~1360 (2007)
- Fernández-Galaz C, "Long-term food restriction prevents ageing-associated central leptin resistance in wistar rats", Diabetologia, 45, pp.997~1003 (2002)
- Lantz KA, "Inhibition of PTP1B by trodusquemine (MSI-1436) causes fat-specific weight loss in diet-induced obese mice", Obesity (Silver Spring), 18, pp.1516~1523 (2010)
- 최윤정, "Combined Treatment of Betulinic Acid, a PTP1B Inhibitor, with Orthosiphon stamineus Extract Decreases Body Weight in High-Fat–Fed Mice", Journal of Medicinal Food, 16(1), pp.2~8 (2013), 한국식품영양과학회[DOI]
- Wilsey J, "Oral vanadium enhances the catabolic effects of central leptin in young adult rats", Endocrinology, 147, pp.493~501 (2006)
- Shapiro A, "Prevention and reversal of diet-induced leptin resistance with a sugar-free diet despite high fat content", Br J Nutr, 106, pp.390~397 (2011)
- Shapiro A, "The act of voluntary wheel running reverses dietary hyperphagia and increases leptin signaling in ventral tegmental area of aged obese rats", Gerontology, 57, pp.335~342 (2011)
- Kim YW, "Leptin-like effects of MTII are augmented in MSG-obese rats", Regul Pept, 127, pp.63~70 (2005)
- Kim MS, "Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase", Nat Med, 10, pp.727~733 (2004)
- Steinberg GR, "Ciliary neurotrophic factor suppresses hypothalamic AMP-kinase signaling in leptin-resistant obese mice", Endocrinology, 147, pp.3906~3914 (2006)
- Kleinridders A, "MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity", Cell Metab, 10, pp.249~259 (2009)
- Boaz M, "The effect of anti-inflammatory (aspirin and", or statin) therapy on body weight in Type 2 diabetic individuals: EAT, a retrospective study, 2009, pp.26, 708~713
- Cintra DE, "Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity", PLoS One, 7, pp.e30571~ (2012)
- Zhang X, "Hypothalamic IKKbeta", NF-kappaB and ER stress link overnutrition to energy imbalance and obesity, 2008, pp.135, 61~73
- Ozcan U, "Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes", Science, 313, pp.1137~1140 (2006)
- Ozcan L, "Endoplasmic reticulum stress plays a central role in development of leptin resistance", Cell Metab, 9, pp.35~51 (2009)
- Ozcan U, "Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes", Science, 306, pp.457~461 (2004)
- Won JC, "Central administration of an endoplasmic reticulum stress inducer inhibits the anorexigenic effects of leptin and insulin", Obesity (Silver Spring), 17, pp.1861~1865 (2009)
- Oral EA, "Leptin-replacement therapy for lipodystrophy", N Engl J Med, 346, pp.570~578 (2002)
- Cochran E, "Efficacy of recombinant methionyl human leptin therapy for the extreme insulin resistance of the Rabson-Mendenhall syndrome", J Clin Endocrinol Metab, 89, pp.1548~1554 (2004)
- Petersen KF, "Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy", J Clin Invest, 109, pp.1345~1350 (2002)
- Welt CK, "Recombinant human leptin in women with hypothalamic amenorrhea", N Engl J Med, 351, pp.987~997 (2004)
- Zelissen PM, "Effect of three treatment schedules of recombinant methionyl human leptin on body weight in obese adults: a randomized, placebo-controlled trial", Diabetes Obes Metab, 7, pp.755~761 (2005)
- Rosenbaum M, "Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight", J Clin Invest, 115, pp.3579~3586 (2005)
- Schurgin S, "Endocrine and metabolic effects of physiologic r-metHu-Leptin administration during acute caloric deprivation in normal-weight women", J Clin Endocrinol Metab, 89, pp.5402~5409 (2004)
- Magkos F, "Leptin replacement improves postprandial glycemia and insulin sensitivity in human immunodeficiency virus-infected lipoatrophic men treated with pioglitazone:a pilot study", Metabolism, 60, pp.1045~1049 (2011)
- Chou SH, "Leptin is an effective treatment for hypothalamic amenorrhea", Proc Natl Acad Sci USA, 108, pp.6585~6590 (2011)
