TITLE

Hepatic Gene Expression Profiling Reveals Key Pathways Involved in Leptin-Mediated Weight Loss in ob/ob Mice

AUTHOR(S)
Sharma, Ashok; Bartell, Shoshana M.; Baile, Clifton A.; Bo Chen; Podolsky, Robert H.; McIndoe, Richard A.; Jin-Xiong She
PUB. DATE
August 2010
SOURCE
PLoS ONE;2010, Vol. 5 Issue 8, p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background: Leptin, a cytokine-like protein, plays an important role in the regulation of body weight through inhibition of food intake and stimulation of energy expenditure. Leptin circulates in blood and acts on the brain, which sends downstream signals to regulate body weight. Leptin therapy has been successful in treating leptin deficient obese patients. However, high levels of leptin have been observed in more common forms of obesity indicating a state of leptin resistance which limits the application of leptin in the treatment of obesity. If the central effect of leptin could be by-passed and genes which respond to leptin treatment could be regulated directly, new therapeutic targets for the treatment of obesity may be possible. The purpose of this study was to identify genes and subsequent pathways correlated with leptin-mediated weight loss. Methodology/Principal Findings: We utilized microarray technology to compare hepatic gene expression changes after two types of leptin administration: one involving a direct stimulatory effect when administered peripherally (subcutaneous: SQ) and another that is indirect, involving a hypothalamic relay that suppresses food intake when leptin is administered centrally (intracerebroventricular: ICV). We identified 214 genes that correlate with leptin mediated weight loss. Several biological processes such as mitochondrial metabolic pathways, lipid metabolic and catabolic processes, lipid biosynthetic processes, carboxylic acid metabolic processes, iron ion binding and glutathione S-transferases were downregulated after leptin administration. In contrast, genes involved in the immune system inflammatory response and lysosomal activity were found to be upregulated. Among the cellular compartments mitochondrion (32 genes), endoplasmic reticulum (22 genes) and vacuole (8 genes) were significantly over represented. Conclusions/Significance: In this study we have identified key molecular pathways and downstream genes which respond to leptin treatment and are involved in leptin-mediated weight loss. Many of these genes have previously been shown to be associated with obesity; however, we have also identified a number of other novel target genes. Further investigation will be required to assess the possible use of these genes and their associated protein products as therapeutic targets for the treatment of obesity.
ACCESSION #
56576672

 

Related Articles

  • Subtyping obesity with microarrays: implications for the diagnosis and treatment of obesity. Wang, S.; Sparks, L. M.; Xie, H.; Greenway, F. L.; de Jonge, L.; Smith, S. R. // International Journal of Obesity;Apr2009, Vol. 33 Issue 4, p481 

    Objective:Obese patients respond differently to weight loss interventions. No efficient diagnostic tool exists to separate obese patients into subtypes as a means to improve prediction of response to interventions. We aimed to separate obese subjects into distinct subgroups using microarray...

  • Leptin reverses declines in satiation in weight-reduced obese humans. Kissileff, Harry R.; Thornton, John C.; Torres, Migdalia I.; Pavlovich, Katherine; Mayer, Laurel S.; Kalari, Vamsi; Leibel, Rudolph L.; Rosenbaum, Michael // American Journal of Clinical Nutrition;Feb2012, Vol. 95 Issue 2, p309 

    Background: Individuals who are weight-reduced or leptin deficient have a lower energy expenditure coupled with higher hunger and disinhibition and/or delayed satiation compared with never-weight-reduced control subjects. Because exogenous leptin inhibits feeding in congenitally leptin-deficient...

  • A New Genetic Clue in Human Obesity: Constitutional Microdeletions of 16p11.2.  // Journal of the Association of Genetic Technologists;2012 2nd Quarter, Vol. 38 Issue 2, p59 

    The article reports that rare constitutional microdeletions of 16p11.2 are the new genetic abnormalities recognized in human obesity. It details that the SH2B1, a candidate gene, mediates the functions of the hormone leptin in the hypothalamus that controls body weight, energy expenditure and...

  • Intuitive eating: An emerging approach to eating behavior. Cadena-Schlam, Leslie; López-Guimerà, Gemma // Nutricion Hospitalaria;mar2015, Vol. 31 Issue 3, p995 

    Introduction: In an effort to treat obesity, health care professionals pursue, by means of dieting and exercise interventions, weight loss as a primary goal of treatment. Although in few cases these interventions induce short-term moderate weight loss, in the long-term, the efficacy of these...

  • Regulation of mouse hepatic genes in response to diet induced obesity, insulin resistance and fasting induced weight reduction. Raab, R. Michael; Bullen, John; Kelleher, Joanne; Mantzoros, Christos; Stephanopoulos, Gregory // Nutrition & Metabolism;2005, Vol. 2, p15 

    Background: Obesity is associated with insulin resistance that can often be improved by caloric restriction and weight reduction. Although many physiological changes accompanying insulin resistance and its treatment have been characterized, the genetic mechanisms linking obesity to insulin...

  • Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. Berglund, Eric D.; Vianna, Claudia R.; Donato Jr., Jose; Kim, Mi Hwa; Jen-Chieh Chuang; Lee, Charlotte E.; Lauzon, Danielle A.; Lin, Peagan; Brule, Laura J.; Scott, Michael M.; Coppari, Roberto; Elmquist, Joel K. // Journal of Clinical Investigation;Mar2012, Vol. 122 Issue 3, p1000 

    Leptin action on its receptor (LEPR) stimulates energy expenditure and reduces food intake, thereby lowering body weight. One leptin-sensitive target cell mediating these effects on energy balance is the proopiomelanocortin (POMC) neuron. Recent evidence suggests that the action of leptin on...

  • Leptin Responsiveness of Mice Deficient in Corticotrophin-Releasing Hormone Receptor Type 2. Harris, Ruth B. S. // Neuroendocrinology;Oct2010, Vol. 92 Issue 3, p198 

    Leptin acts centrally to inhibit food intake and increase energy expenditure. Corticotrophin-releasing hormone (CRH) is one of the neuropeptides that may contribute to leptin-induced hypophagia and thermogenesis. Acute leptin administration increases CRH mRNA expression in the paraventricular...

  • PDK1-Foxo 1 in Agouti-Related Peptide Neurons Regulates Energy Homeostasis by Modulating Food Intake and Energy Expenditure. Yongheng Cao; Nakata, Masanori; Okamoto, Shiki; Takano, Eisuke; Yada, Toshihiko; Minokoshi, Yasuhiko; Hirata, Yukio; Nakajima, Kazunori; Iskandar, Kristy; Hayashi, Yoshitake; Ogawa, Wataru; Barsh, Gregory S.; Hosoda, Hiroshi; Kangawa, Kenji; Itoh, Hiroshi; Noda, Tetsuo; Kasuga, Masato; Nakae, Jun // PLoS ONE;2011, Vol. 6 Issue 4, p1 

    Insulin and leptin intracellular signaling pathways converge and act synergistically on the hypothalamic phosphatidylinositol- 3-OH kinase/3-phosphoinositide-dependent protein kinase 1 (PDK1). However, little is known about whether PDK1 in agoutirelated peptide (AGRP) neurons contributes to...

  • Self-Reported Versus Actual Caloric Intake.  // Journal of Aging & Physical Activity;Oct1993, Vol. 1 Issue 1, p87 

    The article discusses the study which examines the impact of self-reported diet resistance and daily actual caloric intake on losing weight. Researchers used doubly labeled water, which provides an accurate value estimate of total energy expenditure and measured the components of daily energy...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics