Leptin resistance is associated with hypothalamic leptin receptor mRNA and protein downregulation

Martin, Robin Leigh; Perez, Evelyn; He, Yangang; Dawson, Ralph; Millard, William J.

doi:10.1053/meta.2000.17695

Cited by 111 publications

(100 citation statements)

References 27 publications

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“…The finding of decreased serum levels of sOB-R in NAFLD suggests an increased resistance of peripheral tissues to the action of leptin, due to decreased expression and secretion of the OB-R. This might be in agreement with the proposed leptin resistance in morbidly obese subjects [27][28][29] . In conclusion, this study shows that increased serum concentrations of leptin are involved in NAFLD.…”

Section: Discussionsupporting

confidence: 84%

Serum leptin and soluble leptin receptor in non-alcoholic fatty liver disease

Huang¹,

Fan²,

Hen³

et al. 2008

WJG

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feature of steatosis, and serum leptin seems to increase as hepatocyte steatosis develops. An enhanced release of leptin is accompanied by an decrease in sOB-R concentration, which suggests higher resistance of peripheral tissues towards the action of leptin. INTRODUCTIONLeptin -the ob gene product -is a circulating 16-kDa peptide hormone secreted mainly by adipocytes of white fat tissue. It regulates food intake, body fat, insulin action, thermogenesis, induction of angiogenesis, and modulation of the immune system. Leptin synthesis in adipocytes is regulated by several hormones [1] . Leptin action in peripheral tissues involves interaction with specific transmembrane receptors. The leptin receptor (Ob-R), which is a member of the class-1 cytokine receptor family, may be an important determinant of leptin sensitivity. Ob-R was originally demonstrated in hypothalamic neurons, through which leptin regulates food intake and body weight [2] . Alongside several membrane-bound isoforms of Ob-R, with varying cytoplasmic length and with the same extracellular domain, a soluble form of the leptin receptor (sOb-R) can be demonstrated. sOb-R represents the main leptin-binding compound in plasma, which results in fractions of bound and free leptin in plasma [3] . The balance between the free form, the rapidly bioavailable compartment, and bound leptin regulates leptin bioavailability [4] . However, the precise pathophysiological role of sOb-R has not yet been defined.Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized as a common and potentially severe condition often associated with obesity, type 2 diabetes and Abstract AIM:To determine the role of leptin system in non-alcoholic fatty liver disease (NAFLD) development by delineating the changes in serum levels of leptin and soluble leptin receptor (sOB-R). METHODS:Blood samples were collected from 30 consecutive patients with liver-biopsy-proven NAFLD and 30 patients with cholecystolithiasis (stationary phase) as controls. Serum leptin levels were determined by radioimmunoassay and concentration of sOB-R was measured by ELISA. Body mass index (BMI) was calculated for all subjects, and serum insulin, C-peptide, and lipoprotein levels were also detected. RESULTS:Mean serum leptin level and BMI in the NAFLD group were significantly higher than in the controls (both P < 0.001), but mean sOB-R level was lower in the NAFLD group when compared to the controls. Both men and women in the NAFLD group had higher mean serum leptin levels and lower sOB-R levels than did the men and women in the control group (all P < 0.001). There was a significant negative correlation between serum leptin and sOB-R levels (r = -0.725, P < 0.001). Multivariate analysis showed that the percentage of hepatocyte steatosis, sex, BMI, and homeostasis model assessment of insulin resistance (HOMA IR) were independently related to serum leptin levels. CONCLUSION:Elevated serum leptin seems to be a

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Section: Discussionsupporting

confidence: 84%

Serum leptin and soluble leptin receptor in non-alcoholic fatty liver disease

Huang¹,

Fan²,

Hen³

et al. 2008

WJG

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“…By measuring hypothalamic leptin activity, Wang et al (25) found that in rats made hyperleptinemic by overfeeding, fat mass was abundant and hypothalamic leptin activity increased poorly relative to adenovirus-leptin-treated rats, demonstrating the development of a resistance to leptin by overfeeding. Martin et al (26) induced a decrease in body mass for the first 2 weeks of a long-term administration of leptin in rats and then found that a resistance to leptin developed for the final 2 weeks, and that the hypothalamic leptin receptor mRNA was downregulated. Is leptin the main factor of sObR downregulation?…”

Section: Discussionmentioning

confidence: 99%

Mutations in the Human Leptin and Leptin Receptor Genes as Models of Serum Leptin Receptor Regulation

Lahlou

Issad²,

Lebouc³

et al. 2002

Diabetes

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A part of serum Ob leptin, an adipocyte-secreted peptide, is bound to a soluble Ob receptor (sObR). Immunoreactive sObR was measured in 125 lean or obese control subjects (group 1), 18 individuals with a mutation in the leptin gene impairing leptin secretion (group 2), and 10 individuals with a mutation in the ObR gene, leading to production of a truncated ObR not anchored to cell membranes (group 3). In group 1, sObR levels were negatively correlated with age and BMI in children and with BMI in adults. sObR levels were also negatively correlated with leptin levels. Leptin binding activity and sObR levels coeluted in gel-filtration chromatography. In group 2, sObR levels did not differ from those in lean control subjects and were not correlated with BMI. A single peak was detected in chromatographic fractions. In group 3, sObR levels were high and positively correlated with BMI. Immunoreactive sObR coeluted with leptin binding activity. These data demonstrate that leptin is not needed for ObR gene expression, and they suggest that leptin plays a role in receptor downregulation because sObR levels are negatively correlated with leptin levels and BMI in control subjects, whereas sObR levels are not depressed in obese leptin-deficient or leptin receptor-deficient individuals.

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“…However, we found that neither the acute nor the chronic treatments showed significant alterations in their expressions, except for the response with high level of leptin on the ovarian tissue. In a previous study, the chronic administration of leptin for 4 weeks diminished the expression of the mRNA and protein of leptin receptor in the rat hypothalamus (Martin et al 2000). However, other studies have shown no changes in the expression of leptin receptors after a chronic administration of low doses of leptin for 2 weeks (Pal & Sahu 2003).…”

Section: Ctrlmentioning

confidence: 79%

Leptin modulates the expression of its receptors in the hypothalamic–pituitary–ovarian axis in a differential way

Yorio¹,

Bilbao²,

Pustovrh³

et al. 2008

Journal of Endocrinology

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To investigate the expression of leptin receptors (Ob-R) in the rat hypothalamus-pituitary-ovarian axis, immature rats were treated with eCG/hCG and Ob-R expression was evaluated by western blot analysis. The Ob-R expression increased 24 h after eCG administration in all the tissues assayed. In the hypothalamus, these levels immediately decreased to those obtained without treatment. In the pituitary, the Ob-R expression continued to be elevated 48 h after eCG administration, whereas the hCG injection did not modify these levels. Similar results were obtained with the ovarian long isoform. To assess the effect of leptin on its receptors, Ob-R was assessed in hypothalamus, pituitary and ovarian explants cultured in the presence or absence of leptin (0 . 3-500 ng/ml). In the hypothalamus, we found a biphasic effect: the Ob-R expression was either reduced or increased at low or high concentrations of leptin respectively. LH-releasing hormone secretion increased at 1 ng/ml. In the pituitary, Ob-R increased at 10 or 30 ng/ml of leptin for the long and short isoforms respectively. Leptin also induced an increase in LH release at 30 ng/ml. In the ovarian culture, the presence of leptin produced an increase in Ob-R expression at different ranges of concentrations and a dosedependent biphasic effect on the progesterone production. In conclusion, all these results clearly suggest that leptin is able to modulate the expression of its own receptors in the reproductive axis in a differential way. Moreover, the positive or negative effect that leptin exerts on the ovulatory process may be dependent on this regulation.

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Leptin resistance is associated with hypothalamic leptin receptor mRNA and protein downregulation

Cited by 111 publications

References 27 publications

Serum leptin and soluble leptin receptor in non-alcoholic fatty liver disease

Serum leptin and soluble leptin receptor in non-alcoholic fatty liver disease

Mutations in the Human Leptin and Leptin Receptor Genes as Models of Serum Leptin Receptor Regulation

Leptin modulates the expression of its receptors in the hypothalamic–pituitary–ovarian axis in a differential way

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