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Dissecting Long-Term Glucose Metabolism Identifies New Susceptibility Period for Metabolic Dysfunction in Aged Mice.

Chauhan A, Weiss H, Koch F, Ibrahim SM, Vera J, Wolkenhauer O, Tiedge M - PLoS ONE (2015)

Bottom Line: The model predicted a second rise in glucose between 15 and 21 months, which could be experimentally confirmed as a secondary peak.We therefore hypothesize that these two peaks correspond to two sensitive periods of life, where perturbations to the basal metabolism can mark the system for vulnerability to pathologies at later age.Further mathematical modeling may perspectively allow the design of targeted periods for therapeutic interventions and could predict effects on weight loss and insulin levels under conditions of pre-diabetic obesity.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Biology and Bioinformatics, Institute of Computer Science, University of Rostock, Rostock, Germany. Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, Stellenbosch, South Africa.

ABSTRACT
Metabolic disorders, like diabetes and obesity, are pathogenic outcomes of imbalance in glucose metabolism. Nutrient excess and mitochondrial imbalance are implicated in dysfunctional glucose metabolism with age. We used conplastic mouse strains with defined mitochondrial DNA (mtDNA) mutations on a common nuclear genomic background, and administered a high-fat diet up to 18 months of age. The conplastic mouse strain B6-mtFVB, with a mutation in the mt-Atp8 gene, conferred β-cell dysfunction and impaired glucose tolerance after high-fat diet. To our surprise, despite of this functional deficit, blood glucose levels adapted to perturbations with age. Blood glucose levels were particularly sensitive to perturbations at the early age of 3 to 6 months. Overall the dynamics consisted of a peak between 3-6 months followed by adaptation by 12 months of age. With the help of mathematical modeling we delineate how body weight, insulin and leptin regulate this non-linear blood glucose dynamics. The model predicted a second rise in glucose between 15 and 21 months, which could be experimentally confirmed as a secondary peak. We therefore hypothesize that these two peaks correspond to two sensitive periods of life, where perturbations to the basal metabolism can mark the system for vulnerability to pathologies at later age. Further mathematical modeling may perspectively allow the design of targeted periods for therapeutic interventions and could predict effects on weight loss and insulin levels under conditions of pre-diabetic obesity.

No MeSH data available.


Related in: MedlinePlus

Model for diet-induced long-term glucose metabolism.Blood glucose levels (G) and body weight (BW) are regulated by overall energy balance of the body, which is defined by energy intake (Ein) (a) and -expenditure (Eout) (b). Ein depends on diet and demand for food intake (FI) (c1). FI is negatively regulated by elevated insulin (Is) and leptin (Ls) levels. Eout is determined by BW (d) and increased energy expenditure, via Is and Ls, forming a delayed-negative-feedback loop (c2). When Ein is in excess, BW and fat mass (FM) increase. Increased fat mass induces the secretion of both Is and Ls (e). Is levels are also linearly regulated by G (h). Ls and Is also coregulate each other in a positive-feedback loop manner (f), (g).
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pone.0140858.g002: Model for diet-induced long-term glucose metabolism.Blood glucose levels (G) and body weight (BW) are regulated by overall energy balance of the body, which is defined by energy intake (Ein) (a) and -expenditure (Eout) (b). Ein depends on diet and demand for food intake (FI) (c1). FI is negatively regulated by elevated insulin (Is) and leptin (Ls) levels. Eout is determined by BW (d) and increased energy expenditure, via Is and Ls, forming a delayed-negative-feedback loop (c2). When Ein is in excess, BW and fat mass (FM) increase. Increased fat mass induces the secretion of both Is and Ls (e). Is levels are also linearly regulated by G (h). Ls and Is also coregulate each other in a positive-feedback loop manner (f), (g).

Mentions: Fig 2 shows the network of key regulators, operating at several organ levels, in controlling the glucose homeostasis. Glucose homeostasis induced by high-fat diet, involves various processes taking place at different organ levels, including the brain, liver, pancreas and adipose tissues. While liver and pancreas play a central role in glucose metabolism, the adipose tissue is specialized in storing glucose as fat [8]. Additionally, the brain, is able to observe excessive energy signals to modulate glucose and energy homeostasis [9]. Over nutrition leads to a metabolic state characterized by a strongly elevated energy intake, which exceeds energy expenditure. This situation results in accelerated fat mass buildup, which induces rise in leptin levels [10]. Leptin is circulating in blood in proportion to body fat mass [11]. The brain senses the excess fat mass through changes in leptin levels. The primary role of leptin is as negative feedback regulator of diet-induced energy levels. Accumulating evidences have established an analogous role of insulin in diet-induced energy homeostasis [10]. Also, insulin and leptin have been found to share several intracellular and neuronal signaling pathways [12] Based on this knowledge, we model insulin and leptin as redundant pathways, which signal brain to suppress hunger in response to increased fat, while simultaneously increasing energy expenditure by other tissues. Serum insulin is induced by increase in fat mass as well as directly regulated by blood glucose levels [13]. Additionally, we assume a positive feedback between insulin and leptin, based on the studies that insulin positively regulates the leptin levels [14,15,16,17] and that leptin positively regulates insulin levels [18,16,19] (Fig 2).


Dissecting Long-Term Glucose Metabolism Identifies New Susceptibility Period for Metabolic Dysfunction in Aged Mice.

Chauhan A, Weiss H, Koch F, Ibrahim SM, Vera J, Wolkenhauer O, Tiedge M - PLoS ONE (2015)

Model for diet-induced long-term glucose metabolism.Blood glucose levels (G) and body weight (BW) are regulated by overall energy balance of the body, which is defined by energy intake (Ein) (a) and -expenditure (Eout) (b). Ein depends on diet and demand for food intake (FI) (c1). FI is negatively regulated by elevated insulin (Is) and leptin (Ls) levels. Eout is determined by BW (d) and increased energy expenditure, via Is and Ls, forming a delayed-negative-feedback loop (c2). When Ein is in excess, BW and fat mass (FM) increase. Increased fat mass induces the secretion of both Is and Ls (e). Is levels are also linearly regulated by G (h). Ls and Is also coregulate each other in a positive-feedback loop manner (f), (g).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4634931&req=5

pone.0140858.g002: Model for diet-induced long-term glucose metabolism.Blood glucose levels (G) and body weight (BW) are regulated by overall energy balance of the body, which is defined by energy intake (Ein) (a) and -expenditure (Eout) (b). Ein depends on diet and demand for food intake (FI) (c1). FI is negatively regulated by elevated insulin (Is) and leptin (Ls) levels. Eout is determined by BW (d) and increased energy expenditure, via Is and Ls, forming a delayed-negative-feedback loop (c2). When Ein is in excess, BW and fat mass (FM) increase. Increased fat mass induces the secretion of both Is and Ls (e). Is levels are also linearly regulated by G (h). Ls and Is also coregulate each other in a positive-feedback loop manner (f), (g).
Mentions: Fig 2 shows the network of key regulators, operating at several organ levels, in controlling the glucose homeostasis. Glucose homeostasis induced by high-fat diet, involves various processes taking place at different organ levels, including the brain, liver, pancreas and adipose tissues. While liver and pancreas play a central role in glucose metabolism, the adipose tissue is specialized in storing glucose as fat [8]. Additionally, the brain, is able to observe excessive energy signals to modulate glucose and energy homeostasis [9]. Over nutrition leads to a metabolic state characterized by a strongly elevated energy intake, which exceeds energy expenditure. This situation results in accelerated fat mass buildup, which induces rise in leptin levels [10]. Leptin is circulating in blood in proportion to body fat mass [11]. The brain senses the excess fat mass through changes in leptin levels. The primary role of leptin is as negative feedback regulator of diet-induced energy levels. Accumulating evidences have established an analogous role of insulin in diet-induced energy homeostasis [10]. Also, insulin and leptin have been found to share several intracellular and neuronal signaling pathways [12] Based on this knowledge, we model insulin and leptin as redundant pathways, which signal brain to suppress hunger in response to increased fat, while simultaneously increasing energy expenditure by other tissues. Serum insulin is induced by increase in fat mass as well as directly regulated by blood glucose levels [13]. Additionally, we assume a positive feedback between insulin and leptin, based on the studies that insulin positively regulates the leptin levels [14,15,16,17] and that leptin positively regulates insulin levels [18,16,19] (Fig 2).

Bottom Line: The model predicted a second rise in glucose between 15 and 21 months, which could be experimentally confirmed as a secondary peak.We therefore hypothesize that these two peaks correspond to two sensitive periods of life, where perturbations to the basal metabolism can mark the system for vulnerability to pathologies at later age.Further mathematical modeling may perspectively allow the design of targeted periods for therapeutic interventions and could predict effects on weight loss and insulin levels under conditions of pre-diabetic obesity.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Biology and Bioinformatics, Institute of Computer Science, University of Rostock, Rostock, Germany. Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, Stellenbosch, South Africa.

ABSTRACT
Metabolic disorders, like diabetes and obesity, are pathogenic outcomes of imbalance in glucose metabolism. Nutrient excess and mitochondrial imbalance are implicated in dysfunctional glucose metabolism with age. We used conplastic mouse strains with defined mitochondrial DNA (mtDNA) mutations on a common nuclear genomic background, and administered a high-fat diet up to 18 months of age. The conplastic mouse strain B6-mtFVB, with a mutation in the mt-Atp8 gene, conferred β-cell dysfunction and impaired glucose tolerance after high-fat diet. To our surprise, despite of this functional deficit, blood glucose levels adapted to perturbations with age. Blood glucose levels were particularly sensitive to perturbations at the early age of 3 to 6 months. Overall the dynamics consisted of a peak between 3-6 months followed by adaptation by 12 months of age. With the help of mathematical modeling we delineate how body weight, insulin and leptin regulate this non-linear blood glucose dynamics. The model predicted a second rise in glucose between 15 and 21 months, which could be experimentally confirmed as a secondary peak. We therefore hypothesize that these two peaks correspond to two sensitive periods of life, where perturbations to the basal metabolism can mark the system for vulnerability to pathologies at later age. Further mathematical modeling may perspectively allow the design of targeted periods for therapeutic interventions and could predict effects on weight loss and insulin levels under conditions of pre-diabetic obesity.

No MeSH data available.


Related in: MedlinePlus