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Title: The Role of Leptin in Obesity-Induced Hypertension

Authors: Sarah Miraaj-Raza, Erika J. Pearce, Chuku Okorie, Amitabha Ray

Topic: Medicine

Abstract:

Obesity is linked with the growth of white adipose tissue and associated chronic hyperleptinemia. Leptin is a hormone-like cytokine or adipokine secreted mainly from adipose tissue. High leptin state in obesity rapidly causes selective resistance, focused in the arcuate nucleus of the hypothalamus, and centered round leptin’s role in food intake and satiety. This resistance lowers the body’s reaction to food intake and prevents the anorexigenic effects of leptin. As this resistance builds up, the intake of food increases causing an enhancement in body adiposity and leptin levels. However, some pathways do not build resistance to leptin and continue to exhibit the stimulatory effects, which cause a persistent stimulation of sympathetic nervous system (SNS), particularly in the kidneys and skeletal muscles. The increase in SNS activity in the kidney, along with the endothelial dysfunction and oxidative stress, lead to an increase in blood pressure. Apart from leptin's effects on SNS and renal function, this adipokine influences vascular health and hypertension through several phenomena or mechanisms such as baroreflex sensitivity, release of nitric oxide and cardiac hormones. In this review, an attempt has been made to highlight different aspects of leptin biology, which are relevant to hypertension.

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    COMMENT - 1

  • Bhavita Patel (Viewer) 17th Nov 2015 - 11:00 PM
    Hii.....Can you please give me some idea about what is the normal range of leptin & by which method leptin is measured ??
    In obesity does leptin will affect renal function also ??
    regards.
    Bhavita Patel
    • Amitabha Ray (Author) 23rd Nov 2015 - 8:42 PM
      Thank you so much for taking the time to read our article. We greatly appreciate your interest and feedback. The following reference range was taken from Quest Labs (http://www.questdiagnostics.com/hcp/intguide/EndoMetab/EndoManual_AtoZ_PDFs/Leptin.pdf). This lab measures leptin levels using radioimmunoassay (RIA), however, ELISA is also used to measure serum leptin in other labs. Leptin levels have been found to be approximately 4 times higher in obese patients than in patients with normal BMIs [1].

      LEPTIN:
      Reference Range (in ng/mL)
      Adults (BMI 18-25)
      Males: 1.2-9.5
      Adult female: 4.1-25.0
      Children Prepubertal: 1.6-10.8 (Male); 1.7-10.6 (Female)
      Tanner II-III: 2.1-11.6 (Male); .6-11.5 (Female)
      IV-V: 3.4-10.2 (Male); 3.4-13.0 (Female)


      As mentioned in our paper, leptin resistance definitely has an effect on renal function. The leptin resistance found in obesity appears to cause nitric oxide (NO) dysfunction while continuing to stimulate sympathetic nerve activity (SNA). This leads to hypertension with an effective renal stenosis, since the renal vasculature in unable to vasodilate properly. The kidneys then stimulate renin production and the Renin-Angiotensin-Aldosterone System (RAAS) pathway, leading to a right shift in the pressure-natriuresis curve [2, 3].
      Therefore, in summary, obesity induced hyperleptinemia has shown to cause renal leptin resistance which in turn hinders the normal excretion of sodium and water and also plays a role in creating a hypertensive environment.

      1. Silha, J., Krsek, M., Skrha, J., Sucharda, P., Nyomba, B., & Murphy, L. (2003). Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. European Journal of Endocrinology, 149(4), 331-335. doi:10.1530/eje.0.1490331
      2. da Silva, A. A., Do Carmo, J. M., & Hall, J. E. (2013). Role of leptin and CNS melanocortins in obesity hypertension. Current Opinion in Nephrology and Hypertension, 22(2), 135-140.
      3. Haynes, W. G. (2005). Role of leptin in obesity-related hypertension. Experimental Physiology, 90(5), 683-8. doi:10.1113/expphysiol.2005.031237

  • COMMENT - 2

  • Usha Nandini Marimuthu (Viewer) 18th Nov 2015 - 11:30 AM
    The decrease in level of leptin associated with anorexia nervosa causes cessation of menstruation in women of reproductive age group, is there a possibility that the converse is true and that may be the reason for the association of obesity with stein-levithal syndrome (polycystic ovarian syndrome)?
    • Amitabha Ray (Author) 23rd Nov 2015 - 8:42 PM
      Thank you so much for taking the time to read our article. We appreciate your interest and feedback.
      It is really an interesting question; and probably we have no clear answers. Several studies showed conflicting results [1,2]. A considerable number of women with polycystic ovary syndrome (PCOS) are obese. Probably, for this reason, PCOS is commonly linked to insulin resistance and associated leptin resistance (which may interfere with follicular development) [3]. Nevertheless, this combination of leptin and insulin resistance may be important in the development of PCOS.

      1. Rizk NM, Sharif E. Leptin as well as free leptin receptor is associated with polycystic ovary syndrome in young women. Int J Endocrinol. 2015;2015:927805.
      2. Shen SH et al. Obesity and inflammatory biomarkers in women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2015;192:66-71.
      3. Chou SH, Mantzoros C. 20 years of leptin: role of leptin in human reproductive disorders. J Endocrinol. 2014;223:T49-62.
      • Usha Nandini Marimuthu (Viewer) 27th Nov 2015 - 9:10 PM
        Thank you for the reply

  • COMMENT - 3

  • Mr. Matin Ahmad Khan (Viewer) 18th Nov 2015 - 2:26 PM
    Probably other actions of leptin may l also soon be discovered. in the time to come Indeed, Ducy et al. have demonstrated that infusion of leptin into the central nervous system decreased bone mass in mice, suggesting that leptin is also a major regulator of bone formation. It is thus possible that future pharmacological manipulations of the leptin pathway may be a novel therapeutic approach to the treatment of osteoporosis, in addition to affecting blood pressure and obesity.
    Ref: (Ducy P, Amling M, Takeda S et al. Leptin inhibits bone formation through a hypothalamic relay: A central control of bone mass. Cell2000; 100: 197–207)
    • Amitabha Ray (Author) 23rd Nov 2015 - 8:42 PM
      Thank you so much for your interest in our article and for your further insight on the subject of leptin. Though our article has focused on the role of leptin in obesity-induced hypertension, you make a very valid observation that leptin is involved in many other biological functions and its therapeutic role may be far reaching. Physiologically, leptin is one of the major players in the balance of energy intake and energy expenditure. Because leptin resistance has been shown to be selective in the obese state, it causes an imbalance in homeostasis [1]. Finding a means of reversing this resistance has the potential for correcting a number of comorbidities. The case of bone formation and resorption is another area in which leptin appears to have a complex relationship. This complex balancing act that is required of leptin is, we believe, one of the prime reasons that leptin continues to be studied, but its therapeutic uses remain unattainable at this point.

      1. Mantzoros, C. S., Magkos, F., Brinkoetter, M., Sienkiewicz, E., Dardeno, T. A., Kim, S. Y., . . .Hamnvik, O. R. (2011). Leptin in human physiology and pathophysiology. American Journal of Physiology Endocrinology and Metabolism, 301, E567-E584. doi:10.1152/ajpendo.00315.2011

  • COMMENT - 4

  • Surya Narayanan Sethumadavan (Viewer) 19th Nov 2015 - 2:58 PM
    Interesting article. Will this study help in the management of hypertension and obesity?
    • Amitabha Ray (Author) 23rd Nov 2015 - 8:43 PM
      Thank you so much for taking the time to read our article and for your interest in it. The link between leptin resistance and hypertension in obesity has been strongly demonstrated since studies began in the early 1990s and recent research has explored the complexity of the selective leptin resistance in the obese state, which creates a disturbance in the satiation activity of leptin, but does not prevent the increase in energy expenditure (i.e., sympathetic activity), leading to hypertension. Recent studies have been able to uncouple the hypothalamic control of hypertension from the hypothalamic control of satiety, leading to greater insight into selectivity of leptin resistance, particularly in the arcuate nucleus of the hypothalamus. These studies used IKK-β/NF-κBand found that knocking out IKK-β in the arcuate nucleus could reverse leptin resistance and decrease hypertension in mice [1,2]. Better understanding of leptin resistance will definitely help to formulate appropriate strategies in the management of obesity-induced hypertension.


      1. Purkayastha, S., Zhang, G., &Cai, D. (2011). Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB. Nature Medicine, 17(7), 883-887. doi:10.1038/nm.2372
      2. Zhang, X., Zhang, G., Zhang, H., Karin, M., Bai, H., &Cai, D. (2008). Hypothalamic IKKb/Nf-kB and ER stress link overnutrition to energy imbalance and obesity. Cell, 135(1), 61-73. doi:10.1016/j.cell.2008.07.043

  • COMMENT - 5

  • Haseemdeen (Viewer) 23rd Nov 2015 - 6:12 PM
    Very good information abot leptin....is there any way to manage the leptin ?
    • Amitabha Ray (Author) 23rd Nov 2015 - 8:39 PM
      Bhavita Patel:

      Thank you so much for taking the time to read our article. We greatly appreciate your interest and feedback. The following reference range was taken from Quest Labs (http://www.questdiagnostics.com/hcp/intguide/EndoMetab/EndoManual_AtoZ_PDFs/Leptin.pdf). This lab measures leptin levels using radioimmunoassay (RIA), however, ELISA is also used to measure serum leptin in other labs. Leptin levels have been found to be approximately 4 times higher in obese patients than in patients with normal BMIs [1].
      LEPTIN:
      Reference Range (in ng/mL)
      Adults (BMI 18-25)
      Males: 1.2-9.5
      Adult female: 4.1-25.0
      Children Prepubertal: 1.6-10.8 (Male); 1.7-10.6 (Female)
      Tanner II-III: 2.1-11.6 (Male); .6-11.5 (Female)
      IV-V: 3.4-10.2 (Male); 3.4-13.0 (Female)


      As mentioned in our paper, leptin resistance definitely has an effect on renal function. The leptin resistance found in obesity appears to cause nitric oxide (NO) dysfunction while continuing to stimulate sympathetic nerve activity (SNA). This leads to hypertension with an effective renal stenosis, since the renal vasculature in unable to vasodilate properly. The kidneys then stimulate renin production and the Renin-Angiotensin-Aldosterone System (RAAS) pathway, leading to a right shift in the pressure-natriuresis curve [2, 3].
      Therefore, in summary, obesity induced hyperleptinemia has shown to cause renal leptin resistance which in turn hinders the normal excretion of sodium and water and also plays a role in creating a hypertensive environment.

      1. Silha, J., Krsek, M., Skrha, J., Sucharda, P., Nyomba, B., & Murphy, L. (2003). Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. European Journal of Endocrinology, 149(4), 331-335. doi:10.1530/eje.0.1490331
      2. da Silva, A. A., Do Carmo, J. M., & Hall, J. E. (2013). Role of leptin and CNS melanocortins in obesity hypertension. Current Opinion in Nephrology and Hypertension, 22(2), 135-140.
      3. Haynes, W. G. (2005). Role of leptin in obesity-related hypertension. Experimental Physiology, 90(5), 683-8. doi:10.1113/expphysiol.2005.031237.
    • Amitabha Ray (Author) 25th Nov 2015 - 6:01 AM
      To,
      Dr. Haseemdeen,

      Thank you so much for taking the time to read our article and for your interest. To answer your question, leptin analogues, such as metreleptin, have been approved to regulate leptin levels in individuals with congenital leptin deficiency and in individuals with complete lipodystrophy [1]. However, since most of the comorbidities associated with hyperleptinemia are due to the selective resistance to leptin, therapeutic regulation of leptin in these individuals is mainly focused on the reversal of this resistance. Though there are no treatments that are currently available, it is an area that is under considerable study. Our research has led us to propose that the development of an IKK-beta blocker targeted at the arcuate nucleus may be a potential area for further research, and Roujeau, et al. (2014) propose a number of potential therapeutic approaches. Their research found that the co-administration of hormones such as a ligand of LDL receptor-related protein 2 and clusterin, along with the administration of leptin, has shown some promise in the reversal of leptin resistance [2].They also cite Lantz, et al. (2010) who demonstrated that a selective and allosteric inhibitor of PTP1B, trodusquemine, was shown to cross the blood brain barrier and reduced food intake, body weight, and fat mass in mice[3]. Some other areas of study include research into leptin receptor agonists, increasing leptin’s ability to cross the BBB by modification with a trans-activating transcriptional activator (TAT) or by carrying a carbohydrate moiety, increasing cell surface expression of leptin receptors, and decreasing stress on the endoplasmic reticulum [2].


      1. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm387060.htm
      2. Roujeau, C., Jockers, R., & Dam, J. (2014). New Pharmacological Perspectives for the Leptin Receptor in the Treatment of Obesity. Frontiers in Endocrinology, 5. doi:10.3389/fendo.2014.00167
      3. Lantz, K. A., Hart, S. G., Planey, S. L., Roitman, M. F., Ruiz-White, I. A., Wolfe, H. R., & McLane, M. P. (2010). Inhibition of PTP1B by Trodusquemine (MSI-1436) Causes Fat-specific Weight Loss in Diet-induced Obese Mice. Obesity, 18(8), 1516-1523. doi:10.1038/oby.2009.444
    • Amitabha Ray (Author) 25th Nov 2015 - 6:11 AM
      Dear Dr. Haseemdeen,

      The previous reply (on 23rd November) was sent by mistake. Please consider the second one (of 25th November).