Programming into adulthood of islet adaptations induced by early nutritional intervention in the rat

2001 ◽  
Vol 281 (3) ◽  
pp. E640-E648 ◽  
Author(s):  
Ravikumar Aalinkeel ◽  
Malathi Srinivasan ◽  
Fei Song ◽  
Mulchand S. Patel
Keyword(s):  
Adult Life ◽  
Nutritional Intervention ◽  
Milk Formula ◽  
Mrna Levels ◽  
Suckling Period ◽  
Upstream Stimulatory Factor ◽  
Adult Rats ◽  
Phosphatidylinositol Kinase ◽  
Upstream Stimulatory Factor 1 ◽  
Stimulatory Factor

To investigate the influence of a high carbohydrate (HC) intake during the suckling period on pancreatic function in adult life, neonatal rats were artificially reared on a HC milk formula during the preweaning period and then weaned onto lab chow. In the adult HC rat, hyperinsulinemia is sustained by a variety of biochemical and molecular adaptations induced in the HC islets during the suckling period. The adult HC islets showed a distinct left shift in the glucose-stimulated insulin-secretory pattern. HC islets were also able to secrete moderate levels of insulin in the absence of glucose and in the presence of Ca2+channel inhibitors. In addition, the mRNA levels of preproinsulin, somatostatin transcription factor-1, upstream stimulatory factor-1, stress-activated protein kinase-2, phosphatidylinositol kinase, and GLUT-2 genes were significantly increased in HC islets. These results show that consumption of a HC formula during the suckling period programs pancreatic islet function in adult rats, resulting in the maintenance of hyperinsulinemia in the postweaning period and eventually leading to the development of obesity in adult life.

Upstream stimulatory factor 1 associated with familial combined hyperlipidemia, LDL cholesterol, and triglycerides

2005 ◽  
Vol 117 (5) ◽  
pp. 444-451 ◽  
Author(s):  
Hilary Coon ◽  
Yuanpei Xin ◽  
Paul N. Hopkins ◽  
Richard M. Cawthon ◽  
Sandra J. Hasstedt ◽  
...  
Keyword(s):  
Ldl Cholesterol ◽  
Upstream Stimulatory Factor ◽  
Familial Combined Hyperlipidemia ◽  
Upstream Stimulatory Factor 1 ◽  
Stimulatory Factor

Transcriptional regulation of the human cystathionine β-synthase −1b basal promoter: synergistic transactivation by transcription factors NF-Y and Sp1/Sp3

2001 ◽  
Vol 357 (1) ◽  
pp. 97-105 ◽  
Author(s):  
Yubin GE ◽  
Mark A. KONRAD ◽  
Larry H. MATHERLY ◽  
Jeffrey W. TAUB
Keyword(s):  
Reporter Gene ◽  
Intermediate Step ◽  
Nuclear Factor ◽  
Upstream Stimulatory Factor ◽  
E Box ◽  
Gc Box ◽  
Specific Regulation ◽  
Specificity Protein ◽  
Upstream Stimulatory Factor 1 ◽  
Stimulatory Factor

Cystathionine β-synthase (CBS) catalyses the condensation of serine and homocysteine to form cystathionine, an intermediate step in the synthesis of cysteine. Human CBS encodes five distinct 5′ non-coding exons, the most frequent termed CBS −1a and CBS −1b, each transcribed from its own unique GC-rich TATA-less promoter. The minimal transcriptional region (−3792 to −3667) of the CBS −1b promoter was defined by 5′- and 3′-deletions, and transient transfections of reporter gene constructs in HepG2 cells, characterized by CBS transcription exclusively from the −1b promoter. Included in this 125bp region are 3 GC-boxes (termed GC-a, GC-b and GC-c), an inverted CAAT-box and an E-box. By gel-shift and supershift assays, binding of specificity protein (Sp)1 and Sp3 to the GC-box elements, upstream stimulatory factor 1 (USF-1) to the E-box, and both nuclear factor (NF)-Y and an NF-1-like factor to the CAAT box could be demonstrated. By transient trans fections and reporter gene assays in HepG2 and Drosophila SL2 cells, a functional interplay was indicated between NF-Y binding to the CAAT-box, or between USF-1 binding to the E-box, and Sp1/Sp3 binding to the GC-box elements. In SL2 cells, NF-Y and Sp1/Sp3 were synergistic. Furthermore, both Sp1 and the long Sp3 isoform transactivated the CBS −1b minimal promoter; however, the short Sp3 isoforms were potent repressors. These results may explain the cell- or tissue-specific regulation of CBS transcription, and clarify the bases for alterations in CBS gene expression in human disease and Down's syndrome.

Autonomic involvement in the permanent metabolic programming of hyperinsulinemia in the high-carbohydrate rat model

2007 ◽  
Vol 292 (5) ◽  
pp. E1364-E1377 ◽  
Author(s):  
Paul Mitrani ◽  
Malathi Srinivasan ◽  
Catherine Dodds ◽  
Mulchand S. Patel
Keyword(s):  
Insulin Secretion ◽  
Dietary Intervention ◽  
Metabolic Programming ◽  
Milk Formula ◽  
Mrna Levels ◽  
Autonomic Activity ◽  
Suckling Period ◽  
High Carbohydrate ◽  
Type 3

Exposure to a high-carbohydrate (HC) milk formula during the suckling period results in permanent metabolic programming of hyperinsulinemia in HC rats. Previous studies have shown that hyperinsulinemia in HC rats involves a programmed hyperresponsiveness to glucose. However, the immediate onset and persistence of enhanced insulin secretion throughout life suggests a role for numerous factors that control insulin secretion. Present in vivo and in vitro studies have shown a role for altered autonomic activity, including increased parasympathetic and decreased sympathetic activities, in the maintenance of hyperinsulinemia in 100-day-old HC rats. HC rats were shown to be more sensitive to cholinergic-induced potentiation of glucose-stimulated insulin secretion (GSIS) in response to acetylcholine and showed increased sensitivity to blockade of cholinergic-induced insulin secretion by the muscarinic-type 3 receptor-specific antagonist 4-diphenylacetoxy- N-methylpiperidine. In addition, HC rats were less sensitive to adrenergic-induced inhibition of insulin secretion by oxymetazoline, whereas treatment with yohimbine resulted in increased GSIS. Furthermore, HC rats showed greater reductions in plasma insulin levels after vagotomy, as well as an attenuation of yohimbine-induced potentiation of GSIS, suggesting that yohimbine-mediated changes are mediated by parasympathetic activity. Changes in autonomic regulation of GSIS are supported by increased mRNA levels of the parasympathetic signaling molecules muscarinic-type 3 receptor, phospholipase Cβ1, and protein kinase C-α and decreased levels of α2a-adrenergic receptors in islets from adult HC rats. In conclusion, metabolic programming of hyperinsulinemia throughout adulthood of HC rats involves changes in autonomic activity in response to the HC dietary intervention in the suckling period.

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