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Early Metabolic Programming and Calorie Restriction
Amanda and Kiana
Outline
1. Review and Introduction2. Methods3. Results4. Conclusions
Diet and Development
• Pancreatic islets and the hypothalamus mature after birth
• Previous work suggests that early overnutrition leads to metabolic problems in adult rats
What is the effect of calorie restriction on rats that consumed a high-carbohydrate diet early in development?
NPY and POMC
-Increased NPY encourages more food intake-Increased POMC causes satiation-Both of these hormones are regulated by leptin-Located in the arcuate nucleus of the hypothalamus
Schwartz et al. (2000)
Critical Periods of Development
Gestation
Birth
Postnatal-weaning
Brain Development
Development of the Hypothalamus
9-10 weeks
11-14 weeks
15-17 weeks 18-23
weeks
Earliest evidence of NPY neurons at 21 weeks in humans
24-32 weeks
34 weeks to birth
Koutcherov et al. (2002)
Development of the Hypothalamus
Bouret and Simerly (2004)
Development of the hypothalamus in wild-type (WT) and leptin-deficient mice
Pancreatic Islets-Parasympathetic nervous system increases insulin secretion-Parasympathetic nerves are cholinergic- Beta cells within the islet secrete insulin
-Sympathetic nervous system inhibits glucose-related insulin secretion-Sympathetic nerves are adrenergic
Ahren (2000)
Development of the Pancreatic Islets
Development of the Pancreatic Islets in Mice
Cabrera-Vasquez et al. (2009)
Development of the Pancreatic Islets
Cabrera-Vasquez et al. (2009)
Expression of pro-NGF (a Nerve Growth Factor Precursor) in Mouse Pancreatic Islets
Development of the Pancreatic Islets
Signalling Pathways
JAK-STAT Pathway-Stat3 has effects on gene transcription and downregulates the effect of leptin via Socs3-Socs3 is also triggered by inflammation, which can be triggered by diet
Morton and Schwartz (2011)
Signalling Pathways
IRS-PI3K Pathway-Stat3 effects on gene transcription can also be activated through this pathway-Socs3 can affect leptin and insulin signalling
Morton and Schwartz (2011)
Early Diet Influences on Metabolism
STEP 1: Dietary assignments• Postnatal Day 4• Group 1: Motherfed (MF)
• natural rearing on mother’s high fat milk• Group 2: High Carbohydrate (HC)
• artificial rearing on high carb milk
AL - Ad libitum• Unlimited access to food and allowed to eat at will
Postnatal Diets During Suckling Period
MFMother-fed (Control)
HCHigh-Carbohydrate
STEP 2: Change in diet• Postnatal Day 24• Group 1: MF weaned off milk
• standard rat chow ad libitum• Group 2: HC weaned off milk
• standard rat chow ad libitum• Group 3: High Carbohydrate/Pair-fed (HC/PF)
• pair-fed standard rat chowPF - Paired-feeding
HC/PF pups were force fed standard rat chow to match the caloric intake of their paired MF pup
Purpose: to control for caloric intake between the rat pairs
STEP 3: Freedom in feeding• Postnatal Day 90• Group 4: High Carbohydrate/Pair-fed → Ad
libitum (HC/PF/AL)• switch from pair-feeding to free-feeding
Purpose: to observe the effects of caloric restriction on adult-onset obesity
End of Experiment Measures
• Postnatal Day 140• Brains and pancreases dissections• Serum collection for insulin and leptin
concentrations at basal (5.5mM) and max stimulatory (16.7mM) levels
• Insulin secretion 5.5mM glucose alone, +Acetylcholine, and +Oxymetazoline
• mRNA levels of Npy, Pomc, Lepr, Socs3, Stat3
Body Weight Gains of Postnatal Days 24-140
Day 24-52: consistent increase, but no significant difference in body weight change between groups
Day 52-94: consistent increase, HC rats gained significantly more weight than MF and HC/PF
Day 94-108: MF and HC/PF start to level off, HC/PF/AL and HC both increasing
Day 108-140: HC/PF/AL catch up to HC
Srinivasan (2013)
Food Intake by Week
Significant increase at week 12 in HC rats allowed to feed ad libitum No difference between HC and HC/PF/AL
Srinivasan (2013)
Results: Serum Insulin and Leptin
Serum Insulin Levels Serum Leptin Levels
Calorie restriction in adulthood can help maintain a normal metabolic profile.
Islet Response to Glucose
Despite a normal metabolic profile, response of the HC\PF islets to glucose is not normal
Islet Responses
-Acetylcholine application increases insulin production more in the three experimental groups-Oxymetazoline inhibited insulin secretion less in the three experimental groups-Calcium deprivation shows insulin signaling in pancreatic islets is disrupted in experimental groups
mRNA ExpressionExpressed Protein
Pattern Interpretation
NPY HC, HC Pair-fed, and HC/PF/AL pattern together
Metabolic programming
Pomc HC, HC Pair-fed, and HC/PF/AL pattern together
Metabolic programming
Lepr HC and HC/PF/AL pattern together, Mother-fed and pair-fed pattern together
Caloric intake
Stat3 No significant differences between groups with possible trends
Inconclusive
Socs3 HC, HC Pair-fed and HC/PF/AL pattern together
Metabolic Programming
Conclusions
• Calorie restriction creates a similar metabolic profile between MF and HC rats
• Calorie restriction does not change hypothalamic and pancreatic islet signals that lead to obesity in HC rats
• Early high-carb feeding leads to permanent changes in metabolic regulation
• These changes can be modulated by calorie restriction, but not reversed
Works CitedAhren, B. (2000). “Autonomic Regulation of Islet Hormone Secretion -
Implications for Health and Disease.” Diabetologia, 43, p. 393-410. DOI: 10.1007/s001250051322
Bear, M., Connors, B.W., and Paradiso, M.A. (2007). Neuroscience: Exploring the Brain (3rd ed.). Philadelphia, PA: Lippincott Williams & Wilkins.
Bouret, S.G., and Simerly, R.B. (2004). “Minireview: Leptin and Development of Hypothalamic Feeding Circuits.” Endocrinology, 145(6), p. 2621-2626. DOI: 10.1210/en.2004-0231.
Cabrera-Vasquez, S., Navarro-Tableros, V., Sanchez-Soto, C., Gutierrez-Ospina, G., and Hiriart, M. (2009). “Remodelling Sympathetic Innervation in Rat Pancreatic Islets Ontogeny.” BMC Developmental Biology, 9(34), n.p. DOI: 10.1186/1471-213X-9-34.
Works CitedKoutcherov, Y., Mai, J.K., Ashwell, K.W.S., and Paxinos, G. (2002).
“Organization of Human Hypothalamus in Fetal Development.” The Journal of Comparative Neurology, 446, p. 301-324. DOI: 10.1002/cne.10175.
Morton, G.J, and Schwartz, M.W. (2011). “Leptin and Central Nervous System Control of Glucose Metabolism.” Physiological Reviews, 91, p. 389-411. DOI: 10.1152/physrev.00007.2010
Schwartz, M.W., Woods, S.C., Porte Jr., D., Seeley, R.J., and Baskin, D.G. (2000). “Central Nervous System Control of Food Intake.” Nature, 404, p. 661-71. DOI: 10.1038/35007534.
Srinivasan, M., S. Mahmood, and M.S. Patel. (2012). “Metabolic Programming Effects Initiated in the Suckling Period Predisposing for Adult-onset Obesity Cannot Be Reversed by Calorie Restriction.” AJP: Endocrinology and Metabolism 304.5 : E486-494. DOI: 10.1152/ajpendo.00519.2012.
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