Understanding energy balance and body weight regulation requires an understanding of the behavioral and neural evaluation of the oral and post-oral sensory signals involved in the control of food intake within a meal, as well as signals related to the availability of stored fuels. Obesity represents an important dysfunctional state of energy balance, and is frequently accompanied by hyperphagia that is manifested by increased meal size. Two mouse models of obesity, the ob/ob mouse lacking leptin, and the db/db mouse, lacking functional leptin receptors (LEPR-B), are also hyperphagic, and exhibit increased meal size without altered meal frequency relative to wild type lean controls. In the proposed studies, we outline behavioral and immunocytochemical studies designed to elucidate the role of leptin signaling in determining the oral and post-oral sensory influences on ingestion in obesity. These experiments will: 1) characterize the ability of oral and upper gastrointestinal (GI) food stimuli to affect food intake within a meal, 2) assess the degree to which genetic leptin signaling deficiency interferes with the feedback potency of oral and upper GI signals in the control of meal size, and 3) characterize the patterns of central nervous system activation excited by oral and GI stimuli that affect meal size in mice with alterations in leptin signaling. We will focus on the C57B6J mouse as the background strain for these studies because: 1) it is has a well-described tendency toward dietary obesity and, 2) it is the background strain for ob/ob and db/db mice. We will evaluate: 1) the ability of leptin to modify the feedback potency of oral and GI food stimuli in ob/ob mice, 2) the ability of transgenic neuron-specific replacement of LEPR-B to restore normal processing of oral and GI food stimuli in db/db mice, and 3) the effect of central vs. peripheral inducible LEPR-B deficiency on eating in mice. To identify central neuronal regions important in leptin's ability to modulate the processing of food stimuli, we will also evaluate the central nervous system patterns of c-Fos expression in these strains in response to selective oral and/or GI food stimuli. This systematic assessment of meal-related stimuli, their central neural representation, and their integration with energy balance peptide signals will significantly advance our understanding of neuro-humoral interactions in the metabolic control of food intake.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK066618-05
Application #
7373546
Study Section
Special Emphasis Panel (ZRG1-IFCN-4 (94))
Program Officer
Yanovski, Susan Z
Project Start
2004-03-15
Project End
2011-02-28
Budget Start
2008-03-01
Budget End
2011-02-28
Support Year
5
Fiscal Year
2008
Total Cost
$307,255
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Schwartz, Gary J (2013) Central leucine sensing in the control of energy homeostasis. Endocrinol Metab Clin North Am 42:81-7
Blouet, Clemence; Liu, Shun-Mei; Jo, Young-Hwan et al. (2012) TXNIP in Agrp neurons regulates adiposity, energy expenditure, and central leptin sensitivity. J Neurosci 32:9870-7
Schwartz, Gary J (2011) Gut fat sensing in the negative feedback control of energy balance--recent advances. Physiol Behav 104:621-3
Blouet, Clemence; Ono, Hiraku; Schwartz, Gary J (2008) Mediobasal hypothalamic p70 S6 kinase 1 modulates the control of energy homeostasis. Cell Metab 8:459-67
van de Wall, Esther; Leshan, Rebecca; Xu, Allison W et al. (2008) Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion. Endocrinology 149:1773-85
Ono, Hiraku; Pocai, Alessandro; Wang, Yuhua et al. (2008) Activation of hypothalamic S6 kinase mediates diet-induced hepatic insulin resistance in rats. J Clin Invest 118:2959-68
Buettner, Christoph; Muse, Evan D; Cheng, Andrew et al. (2008) Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms. Nat Med 14:667-75
Zizola, Cynthia F; Schwartz, Gary J; Vogel, Silke (2008) Cellular retinol-binding protein type III is a PPARgamma target gene and plays a role in lipid metabolism. Am J Physiol Endocrinol Metab 295:E1358-68
Kim, Ja-Young; van de Wall, Esther; Laplante, Mathieu et al. (2007) Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest 117:2621-37
Zhang, Yiying; Guo, Kaiying; LeBlanc, Robert E et al. (2007) Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms. Diabetes 56:1647-54

Showing the most recent 10 out of 11 publications