In this project, we propose to continue our investigation of the biochemical mechanism(s) by which insulin resistance is acquired. Our long-term focus has been on the link between nutrient availability and insulin action. In this regard, the leptin plays in the regulation of hepatic and peripheral insulin action. However, the biochemical and neural circuitries mediating these effects remain to be elucidated. Here we wish to test the hypothesis that leptin exerts its rapid effects on hepatic glucose fluxes via 2 major central components: ? a) STAT3-dependent effects (mostly leading to rapid stimulation of gluconeogenesis and lipid oxidation); ? b) STAT3-independent effects (mostly leading to rapid inhibition of glycogenolysis and glucose ? output). ? Additionally, more prolonged activation of hypothalamic leptin signaling orchestrates the biological response to nutrient excess by limiting feeding behavior, by increasing energy expenditure and lipid oxidation, and by improving insulin action. Based on preliminary results and on this overall objective we wish to pursue the following specific aims: 1. Does leptin acutely regulate hepatic glucose fluxes via activation of STAT3-independent pathways in the hypothalamus? We will examine whether blocking hypothalamic leptin signaling via STAT3-independent pathways alters leptin action on hepatic nutrient fluxes. 2. Does leptin acutely regulate hepatic glucose fluxes via activation of STAT3-dependent pathways in the hypothalamus? We will examine whether rapid 'loss-of-function' within the hypothalamic STAT3 or melanocortin pathways alters leptin action on hepatic nutrient fluxes. 3. Does leptin acutely inhibit hepatic glucose production via STAT3-independent pathways when its activation of hypothalamic STAT3-dependent pathways is prevented? We will examine whether rapid 'loss-of-function' of STAT3-dependent hypothalamic targets of leptin unveils 'insulin-like' leptin actions on hepatic nutrient fluxes. 4. Does leptin regulate energy balance and insulin action via activation of hypothalamic STAT3-dependent and/or STAT3-independent signaling? We will examine whether week-long manipulations of hypothalamic leptin signaling via selective downstream targets regulate feeding behavior, energy metabolism, and insulin sensitivity. 5. How does short-term over-feeding modify the effects of hypothalamic leptin signaling on hepatic glucose fluxes? We will examine whether short-term stimulation of selective components of hypothalamic leptin signaling 'rescues' the action of leptin on hepatic nutrient fluxes in over-fed rats. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK048321-14
Application #
7237175
Study Section
Metabolism Study Section (MET)
Program Officer
Laughlin, Maren R
Project Start
1994-08-01
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
14
Fiscal Year
2007
Total Cost
$451,304
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
Lontchi-Yimagou, Eric; You, Jee Young; Carey, Michelle et al. (2018) Potential approaches to prevent hypoglycemia-associated autonomic failure. J Investig Med 66:641-647
Carey, Michelle; Gospin, Rebekah; Goyal, Akankasha et al. (2017) Opioid Receptor Activation Impairs Hypoglycemic Counterregulation in Humans. Diabetes 66:2764-2773
Parks, Elizabeth; Yki-Järvinen, Hannele; Hawkins, Meredith (2017) Out of the frying pan: dietary saturated fat influences nonalcoholic fatty liver disease. J Clin Invest 127:454-456
Esterson, Yonah B; Carey, Michelle; Boucai, Laura et al. (2016) Central Regulation of Glucose Production May Be Impaired in Type 2 Diabetes. Diabetes 65:2569-79
Esterson, Yonah B; Carey, Michelle; Piette, John D et al. (2014) A systematic review of innovative diabetes care models in low-and middle-income countries (LMICs). J Health Care Poor Underserved 25:72-93
Davis, Cecilia; Mudd, Jeremy; Hawkins, Meredith (2014) Neuroprotective effects of leptin in the context of obesity and metabolic disorders. Neurobiol Dis 72 Pt A:61-71
Koppaka, Sudha; Kehlenbrink, Sylvia; Carey, Michelle et al. (2013) Reduced adipose tissue macrophage content is associated with improved insulin sensitivity in thiazolidinedione-treated diabetic humans. Diabetes 62:1843-54
Har, Daniel; Carey, Michelle; Hawkins, Meredith (2013) Coordinated regulation of adipose tissue macrophages by cellular and nutritional signals. J Investig Med 61:937-41
Esterson, Yonah B; Zhang, Kehao; Koppaka, Sudha et al. (2013) Insulin sensitizing and anti-inflammatory effects of thiazolidinediones are heightened in obese patients. J Investig Med 61:1152-60
Kishore, P; Kehlenbrink, S; Hu, M et al. (2012) Xylitol prevents NEFA-induced insulin resistance in rats. Diabetologia 55:1808-12

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