Only half the adult rats fed a high energy (HE) diet develop diet-induced obesity (DIO); the rest are diet-resistant (DR), gaining no more weight or fat than chow-fed rats can, however, be separated prospectively by their plasma norepinephrine (NE response to a glucose load thus allowing the study of factors underlying the expression of the DIO/DR phenotypes before HE diet exposure. This proposal will examine brain mechanisms responsible for the differing patterns of weight gain, glucose and lipid metabolism seen in these rats. Emphasis will be placed on brain NE metabolism responsible for the differing patterns of weight gain, glucose and lipid metabolism seen in these rats. Emphasis will be placed on brian NE metabolism and alpha-adrenoreceptor (alpha-AR) binding because these parameters modulate systems important in body weight regulation and because they differ in DIO and DR rats. The diurnal variability of these parameters and in food intake and motor activity will be studied in Sprague-Dawley DIO/DR rats before and after 1mo of HE diet intake to identify early concomitants of the DIO/DR states. Comparison will be made to Fisher F-344 rats, all of which develop an attenuated degree of DIO on HE diet. Acute and chronic intracranial infusions of alpha-AR ligands will test the functional status of DIO versus DR brain alpha-AR's with regard to weight gain, food intake, motor and sympathoadrenal activity, glucose and lipid metabolism, before and after HE diet exposure. Differential sensitivity of brain alpha-AR binding in DIO versus DR rats to altered plasma glucose and food intake levels will also be tested. Finally, transfer of the DR/DIO traits will be attempted by transplanting fetal rat hypothalamus from DIO- to DR-prone rat strains and vice versa, again with emphasis on the role of brain NE metabolism and alpha-AR binding.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK030066-13
Application #
2138300
Study Section
Metabolism Study Section (MET)
Project Start
1982-04-01
Project End
1996-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
13
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Neurosciences
Type
Schools of Medicine
DUNS #
605799469
City
Newark
State
NJ
Country
United States
Zip Code
07107
Levin, Barry E (2017) 10 lessons learned by a misguided physician. Physiol Behav 176:217-222
Johnson, Miranda D; Bouret, Sebastien G; Dunn-Meynell, Ambrose A et al. (2016) Early postnatal amylin treatment enhances hypothalamic leptin signaling and neural development in the selectively bred diet-induced obese rat. Am J Physiol Regul Integr Comp Physiol 311:R1032-R1044
Dunn-Meynell, Ambrose A; Le Foll, Christelle; Johnson, Miranda D et al. (2016) Endogenous VMH amylin signaling is required for full leptin signaling and protection from diet-induced obesity. Am J Physiol Regul Integr Comp Physiol 310:R355-65
Frihauf, Jennifer B; Fekete, Éva M; Nagy, Tim R et al. (2016) Maternal Western diet increases adiposity even in male offspring of obesity-resistant rat dams: early endocrine risk markers. Am J Physiol Regul Integr Comp Physiol 311:R1045-R1059
Otlivanchik, Oleg; Le Foll, Christelle; Levin, Barry E (2015) Perifornical hypothalamic orexin and serotonin modulate the counterregulatory response to hypoglycemic and glucoprivic stimuli. Diabetes 64:226-35
Le Foll, Christelle; Johnson, Miranda D; Dunn-Meynell, Ambrose A et al. (2015) Amylin-induced central IL-6 production enhances ventromedial hypothalamic leptin signaling. Diabetes 64:1621-31
Magnan, Christophe; Levin, Barry E; Luquet, Serge (2015) Brain lipid sensing and the neural control of energy balance. Mol Cell Endocrinol 418 Pt 1:3-8
Cottone, P; Sabino, V; Nagy, T R et al. (2013) Centrally administered urocortin 2 decreases gorging on high-fat diet in both diet-induced obesity-prone and -resistant rats. Int J Obes (Lond) 37:1515-23
Ratner, Cecilia; Ettrup, Anders; Bueter, Marco et al. (2012) Cerebral markers of the serotonergic system in rat models of obesity and after Roux-en-Y gastric bypass. Obesity (Silver Spring) 20:2133-41
Levin, Barry E (2010) Interaction of perinatal and pre-pubertal factors with genetic predisposition in the development of neural pathways involved in the regulation of energy homeostasis. Brain Res 1350:10-7

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