Sharon H. Chou

Narrative Review: The Role of Leptin in Human Physiology: Emerging Clinical Applications

Leptin is a hormone secreted by adipose tissue in direct proportion to amount of body fat. The circulating leptin levels serve as a gauge of energy stores, thereby directing the regulation of energy homeostasis, neuroendocrine function, and metabolism. Persons with congenital deficiency are obese, and treatment with leptin results in dramatic weight loss through decreased food intake and possible increased energy expenditure. However, most obese persons are resistant to the weight-reducing effects of leptin. Recent studies suggest that leptin is physiologically more important as an indicator of energy deficiency, rather than energy excess, and may mediate adaptation by driving increased food intake and directing neuroendocrine function to converse energy, such as inducing hypothalamic hypogonadism to prevent fertilization. Current studies investigate the role of leptin in weight-loss management because persons who have recently lost weight have relative leptin deficiency that may drive them to regain weight. Leptin deficiency is also evident in patients with diet- or exercise-induced hypothalamic amenorrhea and lipoatrophy. Replacement of leptin in physiologic doses restores ovulatory menstruation in women with hypothalamic amenorrhea and improves metabolic dysfunction in patients with lipoatrophy, including lipoatrophy associated with HIV or highly active antiretroviral therapy. The applications of leptin continue to grow and will hopefully soon be used therapeutically.

Leptin is an effective treatment for hypothalamic amenorrhea.

Hypothalamic amenorrhea (HA) is associated with dysfunction of the hypothalamic-pituitary-peripheral endocrine axes, leading to infertility and bone loss, and usually is caused by chronic energy deficiency secondary to strenuous exercise and/or decreased food intake. Energy deficiency also leads to hypoleptinemia, which has been proposed, on the basis of observational studies as well as an open-label study, to mediate the neuroendocrine abnormalities associated with this condition. To prove definitively a causal role of leptin in the pathogenesis of HA, we performed a randomized, double-blinded, placebo-controlled trial of human recombinant leptin (metreleptin) in replacement doses over 36 wk in women with HA. We assessed its effects on reproductive outcomes, neuroendocrine function, and bone metabolism. Leptin replacement resulted in recovery of menstruation and corrected the abnormalities in the gonadal, thyroid, growth hormone, and adrenal axes. We also demonstrated changes in markers of bone metabolism suggestive of bone formation, but no changes in bone mineral density were detected over the short duration of this study. If these data are confirmed, metreleptin administration in replacement doses to normalize circulating leptin levels may prove to be a safe and effective therapy for women with HA.

Lipodystrophy: pathophysiology and advances in treatment

Lipodystrophy is a medical condition characterized by complete or partial loss of adipose tissue. Not infrequently, lipodystrophy occurs in combination with pathological accumulation of adipose tissue at distinct anatomical sites. Patients with lipodystrophy exhibit numerous metabolic complications, which indicate the importance of adipose tissue as an active endocrine organ. Not only the total amount but also the appropriate distribution of adipose tissue depots contribute to the metabolic state. Genetic and molecular research has improved our understanding of the mechanisms underlying lipodystrophy. Circulating levels of hormones secreted by the adipose tissue, such as leptin and adiponectin, are greatly reduced in distinct subpopulations of patients with lipodystrophy. This finding rationalizes the use of these adipokines or of agents that increase their circulating levels, such as peroxisome proliferator-activated receptor γ (PPARγ) agonists, for therapeutic purposes. Other novel therapeutic approaches, including the use of growth hormone and growth-hormone-releasing factors, are also being studied as potential additions to the therapeutic armamentarium. New insights gained from research and clinical trials could potentially revolutionize the management of this difficult-to-treat condition.

Leptin at the Intersection of Neuroendocrinology and Metabolism: Current Evidence and Therapeutic Perspectives

Since its discovery as an adipocyte-secreted hormone, leptin has been found to impact food intake, energy homeostasis, and metabolism through its effects on the central nervous system and peripheral organs. Recent research indicates that leptin may also be involved in cognition, immune function, and bone metabolism. These findings place leptin at the intersection of neuroendocrinology and metabolism, and possibly immune function, and render it an appealing therapeutic target for several niche areas of unmet clinical need. Current evidence regarding classic and emerging roles of leptin as well as the pros and cons of its potential clinical use are summarized herein.

20 YEARS OF LEPTIN: Role of leptin in human reproductive disorders

Leptin, as a key hormone in energy homeostasis, regulates neuroendocrine function, including reproduction. It has a permissive role in the initiation of puberty and maintenance of the hypothalamic-pituitary-gonadal axis. This is notable in patients with either congenital or acquired leptin deficiency from a state of chronic energy insufficiency. Hypothalamic amenorrhea is the best-studied, with clinical trials confirming a causative role of leptin in hypogonadotropic hypogonadism. Implications of leptin deficiency have also emerged in the pathophysiology of hypogonadism in type 1 diabetes. At the other end of the spectrum, hyperleptinemia may play a role in hypogonadism associated with obesity, polycystic ovarian syndrome, and type 2 diabetes. In these conditions of energy excess, mechanisms of reproductive dysfunction include central leptin resistance as well as direct effects at the gonadal level. Thus, reproductive dysfunction due to energy imbalance at both ends can be linked to leptin.

Selective capacity of metreleptin administration to reconstitute CD4+ T-cell number in females with acquired hypoleptinemia

Leptin is an adipocyte-derived hormone that controls food intake and reproductive and immune functions in rodents. In uncontrolled human studies, low leptin levels are associated with impaired immune responses and reduced T-cell counts; however, the effects of leptin replacement on the adaptive immune system have not yet been reported in the context of randomized, controlled studies and/or in conditions of chronic acquired leptin deficiency. To address these questions, we performed a randomized, double-blinded, placebo-controlled trial of recombinant methionyl-human leptin (metreleptin) administration in replacement doses in women experiencing the female triad (hypothalamic amenorrhea) with acquired chronic hypoleptinemia induced by negative energy balance. Metreleptin restored both CD4+ T-cell counts and their in vitro proliferative responses in these women. These changes were accompanied by a transcriptional signature in which genes relevant to cell survival and hormonal response were up-regulated, and apoptosis genes were down-regulated in circulating immune cells. We also observed that signaling pathways involved in cell growth/survival/proliferation, such as the STAT3, AMPK, mTOR, ERK1/2, and Akt pathways, were activated directly by acute in vivo metreleptin administration in peripheral blood mononuclear cells and CD4+ T-cells both from subjects with chronic hypoleptinemia and from normoleptinemic, lean female subjects. Our data show that metreleptin administration, in doses that normalize circulating leptin levels, induces transcriptional changes, activates intracellular signaling pathways, and restores CD4+ T-cell counts. Thus, metreleptin may prove to be a safe and effective therapy for selective CD4+ T-cell immune reconstitution in hypoleptinemic states such as tuberculosis and HIV infection in which CD4+ T cells are reduced.

The Effect of Random Dopant Fluctuations on Logic Timing at Low Voltage

In order to achieve ultra-low power (ULP), ICs are being designed for VDD ≤ 0.5 V. At these low voltages, random dopant fluctuations (RDFs) result in a stochastic component of logic delay that can be comparable to the global corner delay. Moreover, the probability density function (PDF) of this stochastic delay can be highly non-Gaussian. In order to predict the statistical impact of RDF-induced local variations on logic timing, it is necessary to incorporate these effects into a timing closure methodology. This paper presents a computationally efficient methodology for stochastic characterization of standard cell li- braries at low voltage, where the cell delay is a nonlinear function of the transistor random variables (RVs), and the resulting cell delay has a non-Gaussian PDF. It also presents a computation- ally efficient methodology for computing any point on the PDF of a timing path (TP) delay, in the case where cell delays are non-Gaussian. The method is called nonlinear operating point analysis of local variation (NLOPALV). The general NLOPALV theory is developed. It is applied to cell library characterization, and the accuracy of the NLOPALV approach is validated by comparison to Monte Carlo simulation. NLOPALV is also applied to timing path analysis on a 28 nm DSP IC. The approach has been implemented using commercial CAD tools, and integrated into a commercial IC design flow. The NLOPALV approach gives timing results that are within 5% accuracy compared to Monte Carlo analysis at VDD = 0.5 V. This compares to errors on the order of 50% when the Gaussian approximation is used.

Adiponectin Receptor Expression in Human Malignant Tissues

Adiponectin has been proposed to be a mediator of obesity-associated malignancies and to have direct antineoplastic effects acting via adiponectin receptors AdipoR1 and AdipoR2. We describe herein the expression of AdipoR1 and AdipoR2 in several cancers not previously studied. We used immunohistochemistry to assess expression of adiponectin receptors in archival specimens of renal cell carcinoma (n = 64), hepatocellular carcinoma (n = 123), melanoma (n = 20), cholangiocarcinoma (n = 20), transitional cell carcinoma of the bladder (n = 24), ovarian epithelial carcinoma (n = 63), cervical squamous cell carcinoma (n = 49), and adrenocortical carcinoma (n = 48). To compare expression in malignant versus nonmalignant tissues, we also studied AdipoR1 and AdipoR2 expression in pairs of renal cell carcinoma and adjacent healthy kidney tissue specimens by immunohistochemistry. We also studied mRNA expression in 45 specimens of renal cell carcinoma by real-time polymerase chain reaction. Finally, we utilized Western blotting to confirm the presence of adiponectin receptors and subsequently studied cell signaling pathways of adiponectin in the renal cancer cell line 786-O. Cancers associated with obesity were significantly more likely to express AdipoR1 than cancers not associated with obesity. Of the specimens of renal cell carcinoma, which is strongly associated with obesity, 93.8% expressed AdipoR1 compared to 44.9% of the specimens of cervical cell carcinoma, which is not associated with obesity (p < 0.001). There was no difference in the expression of adiponectin receptors or their mRNA between malignant and benign kidney tissue specimens. Overall, there were no correlations between expression of adiponectin receptors or their mRNA and tumor prognostic factors. Finally, Western blotting confirmed the presence of AdipoR1 in the renal cancer cell line 786-O, and adiponectin activates in vitro several signaling pathways in this cell line. In summary, we report for the first time expression of AdipoR1 and AdipoR2 in the above cancers and that AdipoR1 is more ubiquitously expressed in obesity-associated cancers.

An orbital-overlap model for minimal work functions of cesiated metal surfaces.

We introduce a model for the effect of cesium adsorbates on the work function of transition metal surfaces. The model builds on the classical point-dipole equation by adding exponential terms that characterize the degree of orbital overlap between the 6s states of neighboring cesium adsorbates and its effect on the strength and orientation of electric dipoles along the adsorbate-substrate interface. The new model improves upon earlier models in terms of agreement with the work function-coverage curves obtained via first-principles calculations based on density functional theory. All the cesiated metal surfaces have optimal coverages between 0.6 and 0.8 monolayers, in accordance with experimental data. Of all the cesiated metal surfaces that we have considered, tungsten has the lowest minimum work function, also in accordance with experiments.

The Effect of Leptin Replacement on Parathyroid Hormone, RANKL-Osteoprotegerin Axis, and Wnt Inhibitors in Young Women With Hypothalamic Amenorrhea

CONTEXT Recombinant leptin (metreleptin) treatment restores bone mineral density in women with hypothalamic amenorrhea (HA), a condition characterized by hypoleptinemia, which has adverse impact on bone health. OBJECTIVE The objective of the study was to investigate how metreleptin exerts its positive effect on bone metabolism in humans. DESIGN This was a randomized, double-blinded, placebo-controlled study. SETTING The study was conducted at Beth Israel Deaconess Medical Center (Boston, Massachusetts). PATIENTS AND INTERVENTIONS Women (n = 18) with HA and hypoleptinemia for at least 6 months were randomized to receive either metreleptin or placebo for 36 weeks. Serum samples were obtained at baseline and 12, 24, and 36 weeks of treatment. MAIN OUTCOME MEASURES Circulating levels of leptin, intact PTH (iPTH), receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), sclerostin, dickkopf-1, and fibroblast growth factor-23. RESULTS Metreleptin administration significantly increased leptin levels throughout the treatment period (P = .001). iPTH decreased over the 36 weeks of treatment (P = .01). There was a trend toward a decrease in serum RANKL and increase in serum OPG in the metreleptin-treated group. The RANKL to OPG ratio was significantly decreased within the metreleptin (P = .04) but not the placebo group. Metreleptin had no effect on serum sclerostin, dickkopf-1, and fibroblast growth factor-23. CONCLUSIONS Metreleptin treatment over 36 weeks decreases iPTH and RANKL to OPG ratio levels in hypoleptinemic women with HA.