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  Citation statistics : Table of Contents
   2012| December  | Volume 16 | Issue 9  
    Online since January 4, 2013

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Leptin therapy, insulin sensitivity, and glucose homeostasis
Gilberto Paz-Filho, Claudio Mastronardi, Ma-Li Wong, Julio Licinio
December 2012, 16(9):549-555
Glucose homeostasis is closely regulated not only by insulin, but also by leptin. Both hormones act centrally, regulating food intake and adiposity in humans. Leptin has several effects on the glucose-insulin homeostasis, some of which are independent of body weight and adiposity. Those effects of leptin are determined centrally in the hypothalamus and peripherally in the pancreas, muscles and liver. Leptin has beneficial effects on the glucose-insulin metabolism, by decreasing glycemia, insulinemia and insulin resistance. The understanding of the effects of leptin on the glucose-insulin homeostasis will lead to the development of leptin-based therapies against diabetes and other insulin resistance syndromes. In these review, we summarize the interactions between leptin and insulin, and their effects on the glucose metabolism.
  41 5,881 1,245
Leptin and zinc relation : In regulation of food intake and immunity
Abdulkerim Kasim Baltaci, Rasim Mogulkoc
December 2012, 16(9):611-616
Leptin is synthesized and released by the adipose tissue. Leptin, which carries the information about energy reserves of the body to the brain, controls food intake by acting on neuropeptide Y (NPY), which exercises a food-intake-increasing effect through relevant receptors in the hypothalamus. Zinc deficiency is claimed to result in anorexia, weight loss, poor food efficiency, and growth impairment. The fact that obese individuals have low zinc and high leptin levels suggests that there is a relation between zinc and nutrition, and consequently also between zinc and leptin. Leptin deficiency increases the predisposition to infections and this increase is associated with the impairments in the production of cytokines. Zinc has a key role in the sustenance of immune resistance against infections. Dietary zinc deficiency negatively affects CD +4 cells, Th functions, and consequently, cell-mediated immunity by causing a decrease in the production of IL-2, IF-γ, and TNF-α, which are Th1 products. The relation between zinc and the concerned cytokines in particular, and the fact that leptin has a part in the immune responses mediated by these cytokines demonstrate that an interaction among cellular immunity, leptin and zinc is inevitable. An overall evaluation of the information presented above suggests that there are complex relations among food intake, leptin and zinc on one hand and among cellular immunity, leptin and zinc on the other. The aim of the present review was to draw attention to the possible relation between zinc and leptin in dietary regulation and cellular immunity.
  18 3,614 680
Leptin and cancer: Pathogenesis and modulation
Deep Dutta, Sujoy Ghosh, Kaushik Pandit, Pradip Mukhopadhyay, Subhankar Chowdhury
December 2012, 16(9):596-600
Leptin, a product of Ob gene from adipocytes regulates appetite, energy expenditure and body mass composition by decreasing orexigenic and increasing anorexigenic neuropeptide release from hypothalamus. Research over the past few years have suggested leptin/leptin receptor dysregulation to have a role in the development of a large variety of malignancies like breast ca, thyroid ca, endometrial ca and gastrointestinal malignancies, predominantly through JAK/STAT pathway which modulates PI3K/AKT3 signaling, ERK1/2 signaling, expression of antiapoptotic proteins (like XIAP), systemic inflammation (TNF-α, IL6), angiogenic factors (VEGF) and hypoxia inducible factor-1a (HIF-1a) expression. In this review, the current understanding of leptin's role in carcinogenesis has been elaborated. Also a few agents modulating leptin signaling to inhibit cancer cell growth has been described.
  14 4,357 704
Ghrelin and the central regulation of feeding and energy balance
Alfonso Abizaid, Tamas L Horvath
December 2012, 16(9):617-626
Ghrelin was discovered in 1999 as growth hormone secretagouge released from the gut. Soon after it was recognized that ghrelin is a fundamental driver of appetite in rodents and humans and that its mode of action requires alteration of hypothalamic circuit function. Here we review aspects of ghrelin's action that revolve around the central nervous system with the goal to highlight these pathways in integrative physiology of metabolism regulation including ghrelin's cross-talk with the action of the adipose hormone, leptin.
  11 2,165 421
PVN pathways controlling energy homeostasis
Jennifer W Hill
December 2012, 16(9):627-636
Research into the control of energy balance has tended to focus on discrete brain regions, such as the brainstem, medulla, arcuate nucleus of the hypothalamus, and neocortex. Recently, a larger picture has begun to emerge in which the coordinated communication between these areas is proving to be critical to appropriate regulation of metabolism. By serving as a center for such communication, the paraventricular nucleus of the hypothalamus (PVH) is perhaps the most important brain nucleus regulating the physiological response to energetic challenges. Here we review recent advances in the understanding of the circuitry and function of the PVH.
  11 2,377 389
Stimulation of leptin secretion by insulin
Minglun Tsai, Akihiro Asakawa, Haruka Amitani, Akio Inui
December 2012, 16(9):543-548
Leptin has a crucial role in regulating food intake and maintaining metabolic homeostasis. Although little is known about the process of leptin secretion, insulin, which has an important role in the metabolism of glucose and lipids, is believed to regulate leptin secretion through a posttranscriptional mechanism in the short term, and via glucose metabolism in the long term. The gastric mucosa secretes leptin, but this mechanism has not been completely elucidated. Understanding the mechanism of insulin-regulated leptin secretion could lead to the development of new treatment methods for obesity and its comorbidities, which are serious public health concerns.
  11 2,534 585
Leptin in pediatrics: A hormone from adipocyte that wheels several functions in children
Ashraf T Soliman, Mohamed Yasin, Ahmed Kassem
December 2012, 16(9):577-587
The protein leptin, a pleiotropic hormone regulates appetite and energy balance of the body and plays important roles in controlling linear growth, pubertal development, cardiovascular function, and immunity. Recent findings in the understanding of the structure, functional roles, and clinical significance of conditions with increased and decreased leptin secretion are summarized. Balance between leptin and other hormones is significantly regulated by nutritional status. This balance influences many organ systems, including the brain, liver, and skeletal muscle, to mediate the essential adaptation process. The aim of this review is to summarize the possible physiological functions of leptin and its signaling pathways during childhood and adolescence including control of food intake, energy regulation, growth and puberty, and immunity. Moreover, its secretion and possible roles in the adaptation process during different disease states (obesity, malnutrition, eating disorders, delayed puberty, congenital heart diseases and hepatic disorders) are discussed. The clinical manifestations and the successful management of patients with genetic leptin deficiency and the application of leptin therapy in other diseases including lipodystrophy, states with severe insulin resistance, and diabetes mellitus are discussed.
  10 5,904 782
Leptin, diabetes, and the brain
Thomas H Meek, Gregory J Morton
December 2012, 16(9):534-542
Diabetes is a major worldwide problem. Despite some progress in the development of new antidiabetic agents, the ability to maintain tight glycemic control in order to prevent renal, retinal, and neuropathic complications of diabetes without adverse complications still remains a challenge. Recent evidence suggests, however, that in addition to playing a key role in the regulation of energy homeostasis, the adiposity hormone leptin also plays an important role in the control of glucose metabolism via its actions in the brain. This review examines the role of leptin action in the central nervous system and the mechanisms whereby leptin mediates its effects to regulate glucose metabolism. These findings suggest that defects or dysfunction in leptin signaling may contribute to the etiology of diabetes and raise the possibility that either leptin or downstream targets of leptin may have therapeutic potential for the treatment of diabetes.
  8 4,948 950
Benefits of leptin therapy in HIV patients
Uma Sinha, Keshab Sinharay, Nilanjan Sengupta, Prasanta Mukhopadhyay
December 2012, 16(9):637-643
Leptin therapy in human recombinant form has recently been used in HIV-associated lipodystrophy syndrome on experimental basis in some small short-term clinical trials. It has shown its beneficial effects only in hypoleptinemic HIV-infected patients by causing definite improvement in their insulin sensitivity, glucose tolerance, lipid status, and truncal obesity. Leptin prevents lipotoxicity and activates insulin signaling pathways through several postulated mechanisms. Central leptin insufficiency with peripheral hyperleptinemia has come out to be a significant contributor to the development of obesity and metabolic syndrome. In this article, we will review the basis of leptin therapy in HIV patients, with its promises. However, further larger clinical trials are needed to prove its long-term efficacy in the control of metabolic complications related to HIV therapy.
  6 1,555 207
Metformin; A character actor in the leptin story!
Manash P Baruah, Sanjay Kalra, Salam Ranabir
December 2012, 16(9):532-533
  4 1,780 1,838
Insulin and insulin-like growth factor prevent brain atrophy and cognitive impairment in diabetic rats
Predrag Šerbedžija, Douglas N Ishii
December 2012, 16(9):601-610
There are an estimated 36 million dementia patients worldwide. The anticipated tripling of this number by year 2050 will negatively impact the capacity to deliver quality health care. The epidemic in diabetes is particularly troubling, because diabetes is a substantial risk factor for dementia independently of cerebrovascular disease. There is an urgent need to elucidate the pathogenesis of progressive brain atrophy, the cause of dementia, to allow rational design of new therapeutic interventions. This review summarizes recent tests of the hypothesis that the concomitant loss of insulin and insulin-like growth factors (IGFs) is the dominant cause for age-dependent, progressive brain atrophy with degeneration and cognitive decline. These tests are the first to show that insulin and IGFs regulate adult brain mass by maintaining brain protein content. Insulin and IGF levels are reduced in diabetes, and replacement of both ligands can prevent loss of total brain protein, widespread cell degeneration, and demyelination. IGF alone prevents retinal degeneration in diabetic rats. It supports synapses and is required for learning and memory. Replacement doses in diabetic rats can cross the blood-brain barrier to prevent hippocampus-dependent memory impairment. Insulin and IGFs are protective despite unabated hyperglycemia in diabetic rats, severely restricting hyperglycemia and its consequences as dominant pathogenic causes of brain atrophy and impaired cognition. These findings have important implications for late-onset Alzheimer's disease (LOAD) where diabetes is a major risk factor, and concomitant decline in insulin and IGF activity suggest a similar pathogenesis for brain atrophy and dementia.
  4 1,253 39
Metformin and incretin-based therapies up-regulate central and peripheral Adenosine monophosphate-activated protein affecting appetite and metabolism
Masako Nakano, Akio Inui
December 2012, 16(9):529-531
  2 4,979 3,050
Neuropeptide Y in the noradrenergic neurons induces the development of cardiometabolic diseases in a transgenic mouse model
Suvi T Ruohonen, Ullamari Pesonen, Eriika Savontaus
December 2012, 16(9):569-576
Neuropeptide Y (NPY) is a neuropeptide widely expressed in the brain and a peptide transmitter of sympathetic nervous system (SNS) co-released with noradrenaline (NA) in prolonged stress. Association of a gain-of-function polymorphism in the human NPY gene with dyslipideamia, diabetes and vascular diseases suggests that increased NPY plays a role in the pathogenesis of the metabolic syndrome in humans. In the hypothalamus, NPY plays an established role in the regulation of body energy homeostasis. However, the effects of NPY elsewhere in the brain and in the SNS are less explored. In order to understand the role of NPY co-expressed with NA in the sympathetic nerves and brain noradrenergic neurons, a novel mouse model overexpressing NPY in noradrenergic neurons was generated. The mouse displays metabolic defects such as increased adiposity, hepatosteatosis, and impaired glucose tolerance as well as stress-related hypertension and increased susceptibility to vascular wall hypertrophy. The mouse phenotype closely reflects the findings of the several association studies with human NPY gene polymorphisms, and fits with the previous work on the effects of stress-induced NPY release on metabolism and vasculature. Thus, in addition of promoting feeding and obesity in the hypothalamus, NPY expressed in the noradrenergic neurons in the brain and in the SNS induces the development of cardiometabolic diseases.
  2 1,791 284
Long-term correction of type 1 and 2 diabetes by central leptin gene therapy independent of effects on appetite and energy expenditure
Masako Nakano, Akihiro Asakawa, Akio Inui
December 2012, 16(9):556-561
Adipocyte-derived leptin is a hormone associated with the regulation of energy homeostasis, including glucose metabolism. Hyperleptinemia, induced by the consumption of energy-enriched diets, inhibits leptin transport across the blood-brain barrier, and thereby produces leptin insufficiency in the hypothalamus. As a result of sustained leptin insufficiency, the hypothalamic restraint on pancreatic insulin secretion is lost. Additionally, both glucose metabolism and energy expenditure are also diminished, and both type 1 and type 2 diabetes are induced. A replication-deficient recombinant adeno-associated virus vector engineered to encode the leptin gene (rAVV-LEP) has been used in models of diabetes as a novel therapeutic approach. After rAVV-LEP injection in ob/ob mice, hypothalamic leptin expression was increased, body weight was suppressed, and hyperinsulinemia was ameliorated. Additionally injection of rAVV-LEP into the hypothalamus suppressed the expression of orexigenic neuropeptide Y (NPY) and enhanced anorexigenic pro-opiomelanocortin (POMC) in the arcuate nucleus (ARC) in rats. It is proposed that central leptin gene therapy should be tested clinically to reduce the worldwide epidemic of obesity, diabetes, and shortened life span. In this article, the information has been assembled from published review articles on this topic.
  2 1,839 668
A case for new therapy for diabetes, is it leptin?
Satya P Kalra
December 2012, 16(9):525-528
  - 1,374 8,445
Regulatory role of leptin in glucose and lipid metabolism in skeletal muscle
Yasuhiko Minokoshi, Chitoku Toda, Shiki Okamoto
December 2012, 16(9):562-568
Leptin is a hormone secreted by adipocytes that plays a pivotal role in regulation of food intake, energy expenditure, and neuroendocrine function. Several lines of evidences indicate that independent of the anorexic effect, leptin regulates glucose and lipid metabolism in peripheral tissues in rodents and humans. It has been shown that leptin improves the diabetes phenotype in lipodystrophic patients and rodents. Moreover, leptin suppresses the development of severe, progressive impairment of glucose metabolism in insulin-deficient diabetes in rodents. We found that leptin increases glucose uptake and fatty acid oxidation in skeletal muscle in rats and mice in vivo. Leptin increases glucose uptake in skeletal muscle via the hypothalamic-sympathetic nervous system axis and β-adrenergic mechanism, while leptin stimulates fatty acid oxidation in muscle via AMP-activated protein kinase (AMPK). Leptin-induced fatty acid oxidation results in the decrease of lipid accumulation in muscle, which can lead to functional impairments called as "lipotoxicity." Activation of AMPK occurs by direct action of leptin on muscle and through the medial hypothalamus-sympathetic nervous system and α-adrenergic mechanism. Thus, leptin plays an important role in the regulation of glucose and fatty acid metabolism in skeletal muscle.
  - 5,632 1,255
The effects of fat mass and obesity-associated gene variants on the body mass index among ethnic groups and in children and adults
Keiko Shinozaki, Masayuki Okuda
December 2012, 16(9):588-595
Genome-wide association analyses have revealed common gene variations related to obesity. Variants of the fat mass and obesity-associated (FTO) gene among more than 40 genes studied were most closely associated with obesity, but the association varies among ethnicities. Moreover, the effect is significant in people of European descent as well as Asians, but less significant among people of African descent. Although the variants were also associated with type 2 diabetes and glucose homeostasis, the associations were attenuated or abolished after adjusting for adiposity. The present review considers our current understanding of the effects of the FTO variants in different ethnic groups and in adults and children.
  - 1,298 295