Showing papers by "Rexford S. Ahima published in 2005"

Central actions of adipocyte hormones

Abstract: 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.

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

Abstract: 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...

Hormonal and Metabolic Defects in a Prader-Willi Syndrome Mouse Model with Neonatal Failure to Thrive

Abstract: Prader-Willi syndrome (PWS) has a biphasic clinical phenotype with failure to thrive in the neonatal period followed by hyperphagia and severe obesity commencing in childhood among other endocrinological and neurobehavioral abnormalities. The syndrome results from loss of function of several clustered, paternally expressed genes in chromosome 15q11-q13. PWS is assumed to result from a hypothalamic defect, but the pathophysiological basis of the disorder is unknown. We hypothesize that a fetal developmental abnormality in PWS leads to the neonatal phenotype, whereas the adult phenotype results from a failure in compensatory mechanisms. To address this hypothesis and better characterize the neonatal failure to thrive phenotype during postnatal life, we studied a transgenic deletion PWS (TgPWS) mouse model that shares similarities with the first stage of the human syndrome. TgPWS mice have fetal and neonatal growth retardation associated with profoundly reduced insulin and glucagon levels. Consistent with growth retardation, TgPWS mice have deregulated liver expression of IGF system components, as revealed by quantitative gene expression studies. Lethality in TgPWS mice appears to result from severe hypoglycemia after postnatal d 2 after depletion of liver glycogen stores. Consistent with hypoglycemia, TgPWS mice appear to have increased fat oxidation. Ghrelin levels increase in TgPWS reciprocally with the falling glucose levels, suggesting that the rise in ghrelin reported in PWS patients may be secondary to a perceived energy deficiency. Together, the data reveal defects in endocrine pancreatic function as well as glucose and hepatic energy metabolism that may underlie the neonatal phenotype of PWS.

The endocrine role of adipose tissue: focus on adiponectin and resistin

Abstract: Purpose of reviewIn addition to storing energy, adipose tissue secretes various proteins including leptin, adiponectin, resistin, cytokines, coagulation and vasoactive peptides. The levels of these ‘adipokines’ are related to adiposity; hence, they could provide molecular mechanisms for diabetes, dy

Adipocytokine Changes Caused by Low-Carbohydrate Compared to Conventional Diets in Obesity

Abstract: Modest weight loss causing a decrease in insulin resistance has been linked to favorable changes in the adipocyte cytokines leptin, adiponectin, and tumor necrosis factor-α (TNF-α), three emerging risk factors of cardiovascular disease. We previously observed a significant reduction in insulin resistance with weight loss in obese subjects on a low-carbohydrate diet. Based on these previous findings, we hypothesize that a low-carbohydrate diet would be more beneficial in changing leptin, TNF-α, and adiponectin than a conventional diet. A total of 75 severely obese (body mass index ≥35 kg/m2) subjects were randomized to instruction of 6 months of a low-carbohydrate diet or a conventional calorie-restricted diet. Serum levels of leptin, TNF-α, TNF-α-soluble receptor 1 (TNF-α SR1), and adiponectin were measured at baseline and after 6 months of dietary intervention. Subjects on low-carbohydrate diets experienced a greater decrease in leptin when compared to conventional dieters (p < 0.001). TNF-α increased si...

Glomerular and Tubular Epithelial Defects in kd/kd Mice Lead to Progressive Renal Failure

Abstract: 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.

9 adipokines in human endotoxemia

Abstract: Purpose A convergence of innate immune and adipose signals is thought to promote metabolic syndrome and atherosclerosis. Indeed, septicemia and experimental endotoxemia induce insulin resistance and metabolic dyslipidemia. However, the role of innate immunity in regulating adipokines, key modulators of insulin resistance and atherosclerosis, is poorly defined in humans. Method A human endotoxemia model was used to examine the impact of activation of innate immunity on resistin, adiponectin and leptin pathways in vivo. Serial whole blood and adipose (subcutaneous biopsies) gene expression (quantitative PCR) as well as plasma levels of adipokines were measured for 24 hours prior to and following intravenous administration of 3 ng/kg endotoxin (LPS) in 20 healthy human volunteers (50% male, 80% Caucasian, mean age 27.3 ± 4.8, inpatient GCRC protocol). Repeated measures analysis of variance was applied to the data. Findings Whole blood resistin mRNA levels (13.7 ± 7.3 fold; F statistic = 47.3, p Conclusions Endotoxemia induces specific and differential effects on adipokine signaling in humans. Strikingly, resistin appears to be a leukocyte, but not adipose, derived inflammatory cytokine in humans, which is vastly increased in response to LPS. In contrast, adiponectin levels are unchanged during endotoxemia, but expression of both adiponectin receptor subtypes is decreased, consistent with an attenuation of adiponectin insulin sensitizing and anti-atherosclerotic signaling in vivo.