? Leptin has potent effects on insulin action, carbohydrate and lipid metabolism, which are largely independent of its effects on feeding behavior. With regard to adipocyte metabolism, leptin leads to a depletion of triglyceride content without a concomitant rise in circulating free fatty acids due to an increase in mitochondrial oxidation and the induction of futile metabolic pathways. Our previous work has revealed that leptin controls adipocyte metabolism by central pathways that descend from the medio-basal hypothalamus (MBH), leading to a strong inhibition of lipogenic gene expression in white adipose tissue (WAT). Remarkably, MBH leptin suppresses the expression and activity of two important transcription factors, sterol-regulatory-element-binding protein-1c (SREBPI-c) and peroxisome proliferator activated receptor (PPAR) gamma, independent of circulating glucose or insulin levels. These effects of central leptin on adipocyte metabolism appear not to require intact signal transducer and activator of transcription (Stat3) signaling, whereas leptin's acute effects on food intake, hepatic glucose fluxes and gonadotropin secretion are lost when Stat3 signaling is prevented.
The aim of this proposal is to delineate the contributions of hypothalamic leptin signaling in controlling adipocyte metabolism. We hypothesize that Stat3 independent effects of leptin play a major role in the regulation of adipocyte metabolism and thereby regulate body adiposity. These studies should lead to a better understanding of the basic biological processes by which central pathways regulate body adiposity independently of food intake. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08DK074873-02
Application #
7288826
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2006-09-20
Project End
2010-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
2
Fiscal Year
2007
Total Cost
$129,465
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Knight, Elysse M; Ruiz, Henry H; Kim, Soong Ho et al. (2016) Unexpected partial correction of metabolic and behavioral phenotypes of Alzheimer's APP/PSEN1 mice by gene targeting of diabetes/Alzheimer's-related Sorcs1. Acta Neuropathol Commun 4:16
La Merrill, Michele A; Sethi, Sunjay; Benard, Ludovic et al. (2016) Perinatal DDT Exposure Induces Hypertension and Cardiac Hypertrophy in Adult Mice. Environ Health Perspect 124:1722-1727
Scherer, Thomas; Lindtner, Claudia; O'Hare, James et al. (2016) Insulin Regulates Hepatic Triglyceride Secretion and Lipid Content via Signaling in the Brain. Diabetes 65:1511-20
Renault, Thibaud T; Floros, Konstantinos V; Elkholi, Rana et al. (2015) Mitochondrial shape governs BAX-induced membrane permeabilization and apoptosis. Mol Cell 57:69-82
Sadahiro, Masato; Erickson, Connor; Lin, Wei-Jye et al. (2015) Role of VGF-derived carboxy-terminal peptides in energy balance and reproduction: analysis of ""humanized"" knockin mice expressing full-length or truncated VGF. Endocrinology 156:1724-38
Shin, Andrew C; Fasshauer, Martin; Filatova, Nika et al. (2014) Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism. Cell Metab 20:898-909
Iwen, K Alexander; Scherer, Thomas; Heni, Martin et al. (2014) Intranasal insulin suppresses systemic but not subcutaneous lipolysis in healthy humans. J Clin Endocrinol Metab 99:E246-51
Eissing, Leah; Scherer, Thomas; Tödter, Klaus et al. (2013) De novo lipogenesis in human fat and liver is linked to ChREBP-β and metabolic health. Nat Commun 4:1528
Lindtner, Claudia; Scherer, Thomas; Zielinski, Elizabeth et al. (2013) Binge drinking induces whole-body insulin resistance by impairing hypothalamic insulin action. Sci Transl Med 5:170ra14
Buettner, Christoph (2012) Is hyperinsulinemia required to develop overeating-induced obesity? Cell Metab 16:691-2

Showing the most recent 10 out of 18 publications