Identification of leptin-induced transcripts in the mouse hypothalamus.

White, David W.; Zhou, Jianghong; Stricker–Krongrad, Alain; Ge, Pei; Morgenstern, Jay P.; Dembski, Marlene; Tartaglia, Louis A.

doi:10.2337/diabetes.49.9.1443

Cited by 11 publications

(8 citation statements)

References 53 publications

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“…The enhanced leptin transgene expression depletes adipose tissue and depresses weight gain by increasing energy expenditures (White et al, 2000; Dhillon et al, 2001a,b; Bagnasco et al, 2002; Dube et al, 2002; Wang et al, 2010c). The injection of rAAV-lep increases hypothalamic leptin expression and moderates diet-induced hyperglycemia, hyperinsulinemia, and skeletal muscle insulin resistance (Buettner et al, 2000; Bagnasco et al, 2003; Lee et al, 2004).…”

Section: Leptin and Gene Therapymentioning

confidence: 99%

The role of leptin in the control of insulin-glucose axis

et al. 2013

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Obesity and diabetes mellitus are great public health concerns throughout the world because of their increasing incidence and prevalence. Leptin, the adipocyte hormone, is well known for its role in the regulation of food intake and energy expenditure. In addition to the regulation of appetite and satiety that recently has attracted much attentions, insight has also been gained into the critical role of leptin in the control of the insulin-glucose axis, peripheral glucose and insulin responsiveness. Since the discovery of leptin, leptin has been taken for its therapeutic potential to obesity and diabetes. Recently, the therapeutic effects of central leptin gene therapy have been reported in insulin-deficient diabetes in obesity animal models such as ob/ob mise, diet-induced obese mice, and insulin-deficient type 1 diabetes mice, and also in patients with inactivating mutations in the leptin gene. Herein, we review the role of leptin in regulating feeding behavior and glucose metabolism and also the therapeutic potential of leptin in obesity and diabetes mellitus.

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Section: Leptin and Gene Therapymentioning

confidence: 99%

The role of leptin in the control of insulin-glucose axis

et al. 2013

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“…Among them, SOCS3 (suppressor of cytokine signaling 3) negatively regulates hypothalamic leptin signaling via the suppression of JAK2 activation and contributes to the development of a leptin-resistant state (15). Previously, White et al (2000) have identified four novel leptin-induced transcripts (LRG-47, T cell-specific guanine nucleotide triphosphate-binding protein, RC10-11, and Stra-13) from a hypothalamic neuronal cell line, GT1-7, stimulated with leptin (16). However, the roles of leptin-induced molecules in feeding behavior and energy metabolism remain unknown except for neuropeptides and SOCS3.…”

Section: The Nucleotide Sequence(s) Reported In This Paper Has Been Smentioning

confidence: 99%

Regulation of Ghrelin Signaling by a Leptin-induced Gene, Negative Regulatory Element-binding Protein, in the Hypothalamic Neurons

Komori

Doi²,

Furuta³

et al. 2010

Journal of Biological Chemistry

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Leptin, the product of the ob gene, plays important roles in the regulation of food intake and body weight through its receptor in the hypothalamus. To identify novel transcripts induced by leptin, we performed cDNA subtraction based on selective suppression of the polymerase chain reaction by using mRNA prepared from the forebrain of leptin-injected ob/ob mice. One of the genes isolated was a mouse homolog of human negative regulatory element-binding protein (NREBP). Its expression was markedly increased by leptin in the growth hormone secretagogue-receptor (GHS-R)-positive neurons of the arcuate nucleus and ventromedial hypothalamic nucleus. The promoter region of GHS-R contains one NREBP binding sequence, suggesting that NREBP regulates GHS-R transcription. Luciferase reporter assays showed that NREBP repressed GHS-R promoter activity in a hypothalamic neuronal cell line, GT1-7, and its repressive activity was abolished by the replacement of negative regulatory element in GHS-R promoter. Overexpression of NREBP reduced the protein expression of endogenous GHS-R without affecting the expression of ob-Rb in GT1-7 cells. To determine the functional importance of NREBP in the hypothalamus, we assessed the effects of NREBP on ghrelin action. Although phosphorylation of AMP-activated protein kinase ␣ (AMPK␣) was induced by ghrelin in GT1-7 cells, NREBP repressed ghrelin-induced AMPK␣ phosphorylation. These results suggest that leptin-induced NREBP is an important regulator of GHS-R expression in the hypothalamus and provides a novel molecular link between leptin and ghrelin signaling.Obesity develops when food intake exceeds compensatory increases in energy expenditure, and energy is accumulated as fat (1). Food intake is controlled by the precise coordination between the neural circuitry and peripheral factors that derive from fat, gut, and pancreas. The peripheral factors transduce their signals by binding to the receptors in the hypothalamus and regulate production of the orexigenic and the anorexigenic peptides in the specific subsets of hypothalamic neurons (2). Thus, the hypothalamus is critical in integrating signals from the peripheral factors in the neural circuitry.Leptin, an adipocyte-derived hormone (3), is a key negative regulator of food intake and energy expenditure. Circulating leptin enters the brain through the blood-brain barrier (4) and exerts its effects through binding to the long form of the leptin receptor ob-Rb (5) expressed in the hypothalamus, including the arcuate nucleus, ventromedial hypothalamic nucleus (VMH), 2 dorsomedial hypothalamic nucleus, lateral hypothalamic nucleus, and paraventricular hypothalamic nucleus (6). For example, in the hypothalamic arcuate nucleus, leptin suppresses food intake via decreased expression of the orexigenic peptides, neuropeptide Y, and agouti-related peptide and increased expression of the anorexigenic peptides, proopiomelanocortin, and cocaine-and amphetamine-regulated transcript (6 -9).Although the administration of leptin reverses obesity caused b...

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“…Daily administration of recombinant leptin can partially or fully reverse these abnormal phenotypes (4 -10). Gene expression profiling in adipose tissue (11,12), skeletal muscle (13), hypothalamus (14), and pituitary (15) has been used to characterize differences in ob/ob and wild-type (wt) lean mice, and the response to leptin at the molecular level. Interestingly, hypercholesterolemia in ob/ob and db/db mice is due to elevated high-density lipoprotein (HDL) 1 levels (16).…”

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confidence: 99%

Transcriptional Profiling Reveals Global Defects in Energy Metabolism, Lipoprotein, and Bile Acid Synthesis and Transport with Reversal by Leptin Treatment in Ob/ob Mouse Liver

Liang

Tall

2001

Journal of Biological Chemistry

145

105

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Leptin, a hormone secreted by adipose tissue, has been shown to have a major influence on hepatic lipid and lipoprotein metabolism. To characterize changes in lipid and lipoprotein gene expression in mouse liver, suppression subtractive hybridization and cDNA microarray analysis were used to identify mRNAs differentially expressed after leptin treatment of ob/ob mice. Ob/ob mice showed a profound decrease in mRNAs encoding genes controlling bile acid synthesis and transport as well as a variety of apolipoprotein genes and hepatic lipase with reversal upon leptin administration, suggesting that leptin coordinately regulates high density lipoprotein and bile salt metabolism. Leptin administration also resulted in decreased expression of genes involved in fatty acid and cholesterol synthesis, glycolysis, gluconeogenesis, and urea synthesis, and increased expression of genes mediating fatty acid oxidation, ATP synthesis, and oxidant defenses. The changes in mRNA expression are consistent with a switch in energy metabolism from glucose utilization and fatty acid synthesis to fatty acid oxidation and increased respiration. The latter changes may produce oxidant stress, explaining the unexpected finding that leptin induces a battery of genes involved in antioxidant defenses. Expression cluster analysis revealed responses of several sets of genes that were kinetically linked. Thus, the mRNA levels of genes involved in fatty acid and cholesterol synthesis are rapidly (<1 h) repressed by leptin administration, in association with an acute decrease in plasma insulin levels and decreased sterol regulator element-binding protein-1 expression. In contrast, genes participating in fatty acid oxidation and ketogenesis were induced more slowly (24 h), following an increase in expression of their common regulatory factor, peroxisome proliferator-activated receptor ␣. However, the regulation of genes involved in high density lipoprotein and bile salt metabolism shows complex kinetics and is likely to be mediated by novel transcription factors.Leptin, a 16-kDa circulating protein synthesized primarily by white adipose tissue, has diverse regulatory roles in animal physiology, influencing energy metabolism, neuroendocrine, immune, and reproductive functions (1, 2). While various isoforms of the leptin receptor are widely expressed, leptin actions on appetite and energy metabolism are thought to be mediated mainly through the receptor with a long intracellular domain present in the central nervous system (1). The binding of leptin to its receptor in the brain leads to the activation of Janus kinases and signal transducers and activators of transcription, thereby altering the expression and release of a number of neuropeptide effectors known to be involved in the control of feeding behavior and energy balance (1, 2).Mice with genetic defects in the leptin signaling pathway (e.g. ob/ob and db/db mice) are obese and infertile, and show reduced activity and body temperature (3). They also exhibit hyperlipidemia, hyperinsulinemia, hypergly...

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Identification of leptin-induced transcripts in the mouse hypothalamus.

Cited by 11 publications

References 53 publications

The role of leptin in the control of insulin-glucose axis

The role of leptin in the control of insulin-glucose axis

Regulation of Ghrelin Signaling by a Leptin-induced Gene, Negative Regulatory Element-binding Protein, in the Hypothalamic Neurons

Transcriptional Profiling Reveals Global Defects in Energy Metabolism, Lipoprotein, and Bile Acid Synthesis and Transport with Reversal by Leptin Treatment in Ob/ob Mouse Liver

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