Circumventing leptin resistance for weight control.

Departments of Neuroscience and Physiology, College of Medicine, University of Florida McKnight Brain Institute, Gainesville, FL 32610-0244, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 05/2001; 98(8):4279-81. DOI: 10.1073/pnas.091101498
Source: PubMed
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: There is increasing evidence of a causal relationship between sleep-disordered breathing and metabolic dysfunction. Metabolic syndrome (MetS), a cluster of risk factors that promote atherosclerotic cardiovascular disease, comprises central obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension, manifestations of altered total body energy regulation. Excess caloric intake is indisputably the key driver of MetS, but other environmental and genetic factors likely play a role; in particular, obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), may induce or exacerbate various aspects of MetS. Clinical studies show that OSA can affect glucose metabolism, cholesterol, inflammatory markers, and nonalcoholic fatty liver disease. Animal models of OSA enable scientists to circumvent confounders such as obesity in clinical studies. In the most widely used model, which involves exposing rodents to IH during their sleep phase, the IH alters circadian glucose homeostasis, impairs muscle carbohydrate uptake, induces hyperlipidemia, and upregulates cholesterol synthesis enzymes. Complicating factors such as obesity or a high-fat diet lead to progressive insulin resistance and liver inflammation, respectively. Mechanisms for these effects are not yet fully understood, but are likely related to energy-conserving adaptations to hypoxia, which is a strong catabolic stressor. Finally, IH may contribute to the morbidity of MetS by inducing inflammation and oxidative stress. Identification of OSA as a potential causative factor in MetS would have immense clinical impact and could improve the management and understanding of both disorders.
    ILAR journal / National Research Council, Institute of Laboratory Animal Resources 02/2009; 50(3):289-306. · 1.58 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We have examined the dose-dependent effects and central action of intraventricular administration of a recombinant adeno-associated virus encoding rat leptin (rAAV-leptin) in suppressing body weight (BW) gain in adult female rats. A low dose of rAAV-leptin (5x10(10) particles) suppressed weight gain (15%) without changing daily food intake (FI), but a twofold higher dose decreased BW by 30% along with a reduction in daily FI. Reduced BW was due to a loss in body adiposity because serum leptin was reduced. Serum insulin levels were decreased (96%) by only the high dose along with a slight reduction in glucose. Uncoupling protein-1 (UCP-1) mRNA expression in brown adipose tissue (BAT), reflecting energy expenditure through thermogenesis, was upregulated to the same magnitude by the two rAAV-leptin doses. We analyzed by in situ hybridization the expression in the hypothalamus of genes encoding the appetite-regulating neuropeptides. Only the high dose decreased expression of neuropeptide Y (NPY), the orexigenic peptide, and increased proopiomelanocortin (POMC), precursor of the an orexigenic peptide, alpha-MSH. Our studies show for the first time that increased availability of leptin within the hypothalamus through central leptin gene therapy dose-dependently decreases weight gain, adiposity, and serum insulin by increasing energy expenditure and decreasing FI. The decrease in FI occurs only when NPY is reduced and alpha-MSH is increased in the hypothalamus by the high dose of rAAV-leptin. Delivery of the leptin gene centrally through rAAV vectors is a viable therapeutic modality for long-term control of weight and metabolic hormones.
    Molecular Therapy 09/2001; 4(2):139-45. · 7.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Electrophysiological studies of isolated smooth muscle cells have revealed a variety of membrane-conductance changes that contribute to depolarization and excitation. These include activation of inward Cl− and nonselective cation currents, and the suppression of several types of outward K+ currents, leading to depolarization and opening of voltage-dependent Ca2+ current. In most cases, several of these mechanisms operate together in the same cell. We now recognize that [Ca2+]u plays a critical role not only in initiating contraction but in regulating membrane-channel activity. Cl− current is Ca2+ activated, and muscarinic nonselective cation current is facilitated by Ca2+. Cl− and nonselective cation channels therefore participate in a positive feedback loop, where elevation of [Ca2+]; by entry across the membrane or by release from internal stores initiates or promotes depolarization, which in turn leads to further influx of Ca2+ through voltage-dependent Ca2+ channels. These features of excitation of smooth muscle differ from established views, where depolarization is the primary event causing Ca2+ entry and contraction.


Available from