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Rexford S Ahima

Publications and source records attributed to Rexford S Ahima.

At least 19 recordsLinked to original sources
PubMed2006

Area postrema neurons are modulated by the adipocyte hormone adiponectin.

Adiponectin is an adipocyte-derived peptide hormone involved in energy homeostasis and the pathogenesis of obesity, including hypertension. Area postrema (AP) lacks a blood-brain barrier and is a critical homeostatic integration center for humoral and neural signals. Here we investigate the role of AP in adiponectin signaling. We show that rat AP expresses AdipoR1 and AdipoR2 adiponectin receptor mRNA. We used current-clamp electrophysiology to investigate whether adiponectin influenced membrane properties of AP neurons and found that approximately 60% of rat AP neurons tested were sensitive to adiponectin. Additional electrophysiology experiments coupled with single-cell reverse transcription-PCR indicated that all neurons that expressed both subtypes of receptor were sensitive to adiponectin, whereas neurons expressing only one subtype were predominantly insensitive. Last, microinjection of adiponectin into AP caused significant increases in arterial blood pressure, with no change in heart rate, suggesting that adiponectin acts at AP to provide a possible link between control of energy homeostasis and cardiovascular function.

Adipocytes↗
PubMed2006

Ghrelin--a new player in glucose homeostasis?

The hormone ghrelin regulates secretion of growth hormone and energy homeostasis. Sun et al (2006), in this issue of Cell Metabolism, demonstrate that ghrelin inhibits insulin secretion. Deletion of ghrelin increased basal insulin level, enhanced glucose-stimulated insulin secretion, and improved peripheral insulin sensitivity. These effects were not related to changes in food intake or weight, suggesting ghrelin has unique actions on key components of glucose homeostasis.

Animals↗
PubMed2006

Adipokines that link obesity and diabetes to the hypothalamus.

Adipose tissue plays a crucial role in energy homeostasis not only in storing triglyceride, but also responding to nutrient, neural, and hormonal signals, and producing factors which control feeding, thermogenesis, immune and neuroendocrine function, and glucose and lipid metabolism. Adipose tissue secretes leptin, steroid hormones, adiponectin, inflammatory cytokines, resistin, complement factors, and vasoactive peptides. The endocrine function of adipose tissue is typified by leptin. An increase in leptin signals satiety to neuronal targets in the hypothalamus. Leptin activates Janus-activating kinase2 (Jak2) and STAT 3, resulting in stimulation of anorexigenic peptides, e.g., alpha-MSH and CART, and inhibition of orexigenic peptides, e.g., NPY and AGRP. The reduction in leptin levels during fasting stimulates appetite, decreases thermogenesis, thyroid and reproductive hormones, and increases glucocorticoids. Leptin also stimulates fatty acid oxidation, insulin release, and peripheral insulin action. These effects involve regulation of PI-3 kinase, PTP-1B, suppressor of cytokine signaling-3 (SOCS-3), and AMP-activated protein kinase in the brain and peripheral organs. There is emerging evidence that leptin, adiponectin, and resistin act through overlapping pathways. Understanding the signal transduction of adipocyte hormones will provide novel insights on the pathogenesis and treatment of obesity, diabetes, and various metabolic disorders.

Adipose Tissue↗
PubMed2006

Metabolic actions of adipocyte hormones: focus on adiponectin.

The obesity epidemic has focused attention on the endocrine function of adipose tissue. Adipose tissue secretes leptin, cytokines, complement factors, and components of the coagulation cascade, most of which are increased in obesity. In contrast, a strong negative correlation exists between adiponectin and adiposity, insulin sensitivity, diabetes, vascular inflammation, and atherosclerosis. Adiponectin treatment in rodents increases insulin sensitivity and reduces lipids and atherogenesis. Chronic and central adiponectin treatment reduces weight, glucose, and lipids. The insulin-sensitizing action of thiazolidinediones is mediated, in part, through adiponectin. A causal role of adiponectin in diabetes, dyslipidemia, and atherosclerosis has been established in knockout mice. Therefore, adiponectin seems to be a marker of obesity-related diseases and a potential therapeutic target.

Adipocytes↗
PubMed2006

Adipose tissue as an endocrine organ.

Adipose tissue plays a critical role in energy homeostasis, not only in storing triglycerides, but also responding to nutrient, neural, and hormonal signals and secreting adipokines that control feeding, thermogenesis, immunity, and neuroendocrine function. A rise in leptin signals satiety to the brain through receptors in hypothalamic and brainstem neurons. Leptin activates tyrosine kinase, Janus kinase 2, and signal transducer and activator of transcription 3, leading to increased levels of anorexigenic peptides, e.g., alpha-melanocyte stimulating hormone and cocaine- and amphetamine-regulated transcript, and inhibition of orexigenic peptides, e.g., neuropeptide Y and agouti-related peptide. Obesity is characterized by hyperleptinemia and hypothalamic leptin resistance, partly caused by induction of suppressor of cytokine signaling-3. Leptin falls rapidly during fasting and potently stimulates appetite, reduces thermogenesis, and mediates the inhibition of thyroid and reproductive hormones and activation of the hypothalamic-pituitary-adrenal axis. These actions are integrated by the paraventicular hypothalamic nucleus. Leptin also decreases glucose and stimulates lipolysis through central and peripheral pathways involving AMP-activated protein kinase (AMPK). Adiponectin is secreted exclusively by adipocytes and has been linked to glucose, lipid, and cardiovascular regulation. Obesity, diabetes, and atherosclerosis have been associated with reduced adiponectin levels, whereas adiponectin treatment reverses these abnormalities partly through activation of AMPK in liver and muscle. Administration of adiponectin in the brain recapitulates the peripheral actions to increase fatty acid oxidation and insulin sensitivity and reduce glucose. Although putative adiponectin receptors are widespread in peripheral organs and brain, it is uncertain whether adiponectin acts exclusively through these targets. As with leptin, adiponectin requires the central melanocortin pathway. Furthermore, adiponectin stimulates fatty acid oxidation and reduces glucose and lipids, at least in part, by activating AMPK in muscle and liver.

Adipocytes↗
PubMed2006

Neuroendocrine and metabolic effects of adipocyte-derived hormones.

Obesity is characterized by an increase in adipose tissue mass. Contrary to the previous view of adipose tissue as simply an inert tissue devoted to energy storage, studies over the past decade have shown that adipose tissue is actively involved in regulating physiological processes and participates in disease. Adipose tissue secretes factors that exert local and systemic effects. Leptin, pro-inflammatory cytokines, resistin and proteins involved in haemodynamic regulation and coagulation are increased in obesity while adiponectin is reduced. The production of active corticosteroids is also increased in obesity. There is now growing evidence that adipocyte secretory factors regulate energy homoeostasis, as well as cardiovascular and immune systems. Some adipocyte hormones, most notably leptin, act in the brain to influence the neuroendocrine axis and energy balance, whereas adiponectin and resistin exert opposing effects on glucose and lipids. Understanding the actions of adipocyte hormones will provide novel insights into the pathophysiology and treatment of obesity.

Adipocytes↗
PubMed2006

Loss of resistin improves glucose homeostasis in leptin deficiency.

Resistin levels are increased in obesity, and hyperresistinemia impairs glucose homeostasis in rodents. Here, we have determined the role of resistin in ob/ob mice that are obese and insulin resistant because of genetic deficiency of leptin. Loss of resistin increased obesity in ob/ob mice by further lowering the metabolic rate without affecting food intake. Nevertheless, resistin deficiency improved glucose tolerance and insulin sensitivity in these severely obese mice, largely by enhancing insulin-mediated glucose disposal in muscle and adipose tissue. In contrast, in C57BL/6J mice with diet-induced obesity but wild-type leptin alleles, resistin deficiency reduced hepatic glucose production and increased peripheral glucose uptake. Resistin deficiency enhanced Akt phosphorylation in muscle and liver and decreased suppressor of cytokine signaling-3 level in muscle, and these changes were reversed by resistin replacement. Together, these results provide strong support for an important role of resistin in insulin resistance and diabetes associated with genetic or diet-induced obesity.

Aging↗
PubMed2006

Neuropeptide Y deficiency attenuates responses to fasting and high-fat diet in obesity-prone mice.

Neuropeptide Y (NPY) stimulates feeding and weight gain, but deletion of the NPY gene does not affect food intake and body weight in mice bred on a mixed genetic background. We reasoned that the orexigenic action of NPY would be evident in C57Bl/6J mice susceptible to obesity. NPY deficiency has no significant effect in mice fed a normal rodent diet. However, energy expenditure is elevated during fasting, and hyperphagia and weight gain are blunted during refeeding. Expression of agouti-related peptide (AGRP) in the hypothalamus is increased in NPY knockout (NPYko) than wild-type mice, but unlike wild type there is no further increase in AGRP when NPYko mice are fasted. Moreover, NPYko mice have higher oxygen consumption and uncoupling protein-1 expression in brown adipose tissue during fasting. The failure of an increase in orexigenic peptides and higher thermogenesis may contribute to attenuation of weight gain when NPYko mice are refed. C57Bl/6J mice lacking NPY are also less susceptible to diet-induced obesity (DIO) as a result of reduced feeding and increased energy expenditure. The resistance to DIO in NPYko mice is associated with a reduction in nocturnal feeding and increased expression of anorexigenic hypothalamic peptides. Insulin, leptin, and triglyceride levels increase with adiposity in both wild-type and NPYko mice.

Aging↗
PubMed2006

Brain adipocytokine action and metabolic regulation.

Adipose tissue secretes factors that control various physiological systems. The fall in leptin during fasting mediates hyperphagia and suppresses thermogenesis, thyroid and reproductive hormones, and immune system. On the other hand, rising leptin levels in the fed state stimulate fatty acid oxidation, decrease appetite, and limit weight gain. These divergent effects of leptin occur through neuronal circuits in the hypothalamus and other brain areas. Leptin also regulates the activities of enzymes involved in lipid metabolism, e.g., AMP-activated protein kinase and stearoyl-CoA desaturase-1, and also interacts with insulin signaling in the brain. Adiponectin enhances fatty acid oxidation and insulin sensitivity, in part by stimulating AMP-activated protein kinase phosphorylation and activity in liver and muscle. Moreover, adiponectin decreases body fat by increasing energy expenditure and lipid catabolism. These effects involve peripheral and possibly central mechanisms. Adipose tissue mediates interconversion of steroid hormones and secretes proinflammatory cytokines, vasoactive peptides, and coagulation and complement proteins. Understanding the actions of these "adipocytokines" will provide insight into the pathogenesis and treatment of obesity and related diseases.

Adiponectin↗
PubMed2005

Glomerular and tubular epithelial defects in kd/kd mice lead to progressive renal failure.

BACKGROUND/AIM: The kd/kd mouse spontaneously develops severe and progressive nephritis leading to renal failure, characterized by cellular infiltration, tubular destruction and glomerular sclerosis. Recent identification of the mutant gene and the observation that podocytes are affected, led to the hypothesis that there are primary renal epithelial cell defects in this strain. METHODS: Clinical and pathological signs of disease in a large cohort of kd/kd mice were studied by light microscopy, electron microscopy, and biochemical analyses of serum and urine at early stages of disease. Special attention was paid to mice under 140 days of age that had normal blood urea nitrogen (BUN) levels, but had developed albuminuria. RESULTS: Although overt glomerular abnormalities are commonly observed either coincident with or after tubulointerstitial nephritis, we now report that albuminuria and visceral epithelial abnormalities, including hyperplasia and podocyte effacement may occur before the onset of either elevated BUN levels or severe interstitial nephritis, and this is accompanied by biochemical perturbations in serum typical of the nephrotic syndrome. CONCLUSIONS: The results suggest that the defect in kd/kd mice primarily affects both the tubular and glomerular visceral epithelium. The tubular epithelial defect triggers autoimmune interstitial nephritis, whereas a defect in podocytes leads to proteinuria and glomerulosclerosis. Thus, a single mitochondrial abnormality may result in differences in disease expression that vary with the type of epithelial cells. It is likely that the mitochrondrial perturbations in glomerular and tubular epithelia act in concert, through activation of different pathologic pathways, to accelerate disease progression leading to renal failure.

Animals↗
PubMed2005

Neuroendocrine profiles associated with energy intake, sleep, and stress in the night eating syndrome.

CONTEXT: Night eating syndrome (NES) is characterized by evening hyperphagia and frequent awakenings with ingestion of food. It is associated with obesity and depressed mood. Greater understanding of hormonal influences on NES is desirable. OBJECTIVE: Our objective was to evaluate 25-h profiles of hormones involved in energy balance, sleep, and stress in NES. DESIGN: Blood assays for glucose, insulin, ghrelin, leptin, melatonin, cortisol, TSH, and prolactin were sampled repeatedly among NES and control subjects. Food intake and depressive symptoms were assessed. SETTING AND PARTICIPANTS: Fifteen NES and 14 matched control participants stayed three nights in a General Clinical Research Center. MAIN OUTCOME MEASURES: We assessed differences between NES and control participants in the 25-h profiles of eight hormones. RESULTS: Nocturnal food intake was higher among NES participants, although their daily calorie intake was similar to that of controls. Reflecting their increased nocturnal intake, insulin (P < 0.001) and glucose levels (P = 0.07) among NES participants were higher than those of controls. Ghrelin levels were significantly lower in NES participants than in controls from 0100-0900 h (P = 0.003). Levels of plasma cortisol, melatonin, leptin, and prolactin did not differ between groups, but there was a trend for TSH levels (P = 0.07) to be higher during the 25 h in NES. NES participants had greater depressive symptoms than controls (P < 0.001). The differences in the levels of glucose, insulin, and ghrelin between NES and controls are closely associated with nocturnal food intake.

Adult↗
PubMed2005

Mouse and human resistins impair glucose transport in primary mouse cardiomyocytes, and oligomerization is required for this biological action.

The adipocytokine resistin impairs glucose tolerance and insulin sensitivity in rodents. Here, we examined the effect of resistin on glucose uptake in isolated adult mouse cardiomyocytes. Murine resistin reduced insulin-stimulated glucose uptake, establishing the heart as a resistin target tissue. Notably, human resistin also impaired insulin action in mouse cardiomyocytes, providing the first evidence that human and mouse resistin homologs have similar functions. Resistin is a cysteine-rich molecule that circulates as a multimer of a dimeric form dependent upon a single intermolecular disulfide bond, which, in the mouse, involves Cys26; mutation of this residue to alanine (C26A) produces a monomeric molecule that appears to be bioactive in the liver. Remarkably, unlike native resistin, monomeric C26A resistin had no effect on basal or insulin-stimulated glucose uptake in mouse cardiomyocytes. Resistin impairs glucose uptake in cardiomyocytes by mechanisms that involve altered vesicle trafficking. Thus, in cardiomyocytes, both mouse and human resistins directly impair glucose transport; and in contrast to effects on the liver, these actions of resistin require oligomerization.

Animals↗
PubMed2005

Foxa2 integrates the transcriptional response of the hepatocyte to fasting.

Survival during prolonged food deprivation depends on the activation of hepatic gluconeogenesis. Inappropriate regulation of this process is a hallmark of diabetes and other metabolic diseases. Activation of the genes encoding gluconeogenic enzymes is mediated by hormone-responsive transcription factors such as the cyclic AMP response element binding protein (CREB) and the glucocorticoid receptor (GR). Here we show using cell-type-specific gene ablation that the winged helix transcription factor Foxa2 is required for activation of the hepatic gluconeogenic program during fasting. Specifically, Foxa2 promotes gene activation both by cyclic AMP, the second messenger for glucagon, and glucocorticoids. Foxa2 mediates these effects by enabling recruitment of CREB and GR to their respective target sites in chromatin. We conclude that Foxa2 is required for execution of the hepatic gluconeogenic program by integrating the transcriptional response of the hepatocyte to hormonal stimulation.

Animals↗
PubMed2005

Central actions of adipocyte hormones.

Adipose tissue secretes a variety of proteins with important roles in metabolism, reproduction, immunity and cardiovascular function. The endocrine function of adipose tissue, especially that of leptin, is linked to energy storage and thus might provide insights into obesity and other diseases associated with energy imbalance. This review highlights the current understanding of the actions of leptin in the brain, with particular emphasis on transport across the blood-brain barrier, signal transduction, neuropeptide targets and roles during fasting and obesity. Moreover, data pertaining to the potential central effects of adiponectin, cytokines and resistin on energy homeostasis, glucose and lipid metabolism are discussed.

Adipocytes↗
PubMed2004

Adiponectin acts in the brain to decrease body weight.

Adiponectin (ADP) is an adipocyte hormone involved in glucose and lipid metabolism. We detected a rise in ADP in cerebrospinal fluid after intravenous (i.v.) injection, consistent with brain transport. In contrast to leptin, intracerebroventricular (i.c.v.) administration of ADP decreased body weight mainly by stimulating energy expenditure. Full-length ADP, mutant ADP with Cys39 replaced with serine, and globular ADP were effective, whereas the collagenous tail fragment was not. Lep(ob/ob) mice were especially sensitive to i.c.v. and systemic ADP, which resulted in increased thermogenesis, weight loss and reduction in serum glucose and lipid levels. ADP also potentiated the effect of leptin on thermogenesis and lipid levels. While both hormones increased expression of hypothalamic corticotropin-releasing hormone (CRH), ADP had no substantial effect on other neuropeptide targets of leptin. In addition, ADP induced distinct Fos immunoreactivity. Agouti (A(y)/a) mice did not respond to ADP or leptin, indicating the melanocortin pathway may be a common target. These results show that ADP has unique central effects on energy homeostasis.

Adiponectin↗