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Hepatic adaptations to maintain metabolic homeostasis in response to fasting and refeeding in mice

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ABSTRACT

Background: The increased incidence of obesity and associated metabolic diseases has driven research focused on genetically or pharmacologically alleviating metabolic dysfunction. These studies employ a range of fasting-refeeding models including 4–24 h fasts, “overnight” fasts, or meal feeding. Still, we lack literature that describes the physiologically relevant adaptations that accompany changes in the duration of fasting and re-feeding. Since the liver is central to whole body metabolic homeostasis, we investigated the timing of the fast-induced shift toward glycogenolysis, gluconeogenesis, and ketogenesis and the meal-induced switch toward glycogenesis and away from ketogenesis.

Methods: Twelve to fourteen week old male C57BL/6J mice were fasted for 0, 4, 8, 12, or 16 h and sacrificed 4 h after lights on. In a second study, designed to understand the response to a meal, we gave fasted mice access to feed for 1 or 2 h before sacrifice. We analyzed the data using mixed model analysis of variance.

Results: Fasting initiated robust metabolic shifts, evidenced by changes in serum glucose, non-esterified fatty acids (NEFAs), triacylglycerol, and β-OH butyrate, as well as, liver triacylglycerol, non-esterified fatty acid, and glycogen content. Glycogenolysis is the primary source to maintain serum glucose during the first 8 h of fasting, while de novo gluconeogenesis is the primary source thereafter. The increase in serum β-OH butyrate results from increased enzymatic capacity for fatty acid flux through β-oxidation and shunting of acetyl-CoA toward ketone body synthesis (increased CPT1 (Carnitine Palmitoyltransferase 1) and HMGCS2 (3-Hydroxy-3-Methylglutaryl-CoA Synthase 2) expression, respectively). In opposition to the relatively slow metabolic adaptation to fasting, feeding of a meal results in rapid metabolic changes including full depression of serum β-OH butyrate and NEFAs within an hour.

Conclusions: Herein, we provide a detailed description of timing of the metabolic adaptations in response to fasting and re-feeding to inform study design in experiments of metabolic homeostasis. Since fasting and obesity are both characterized by elevated adipose tissue lipolysis, hepatic lipid accumulation, ketogenesis, and gluconeogenesis, understanding the drivers behind the metabolic shift from the fasted to the fed state may provide targets to limit aberrant gluconeogenesis and ketogenesis in obesity.

No MeSH data available.


Changes in serum metabolites in response to fasting duration. Serum concentration of a glucose, b non-esterified fatty acid (NEFA), c triacylglycerol (TAG), and d β-OH Butyrate in mice that were fasted for 0, 4, 8, 12, and 16 h. a,b,c,dBars that do not share a common letter differ significantly (P < 0.05; n = 6)
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Fig1: Changes in serum metabolites in response to fasting duration. Serum concentration of a glucose, b non-esterified fatty acid (NEFA), c triacylglycerol (TAG), and d β-OH Butyrate in mice that were fasted for 0, 4, 8, 12, and 16 h. a,b,c,dBars that do not share a common letter differ significantly (P < 0.05; n = 6)

Mentions: Fasting decreased serum glucose levels significantly by 12 h (P < 0.05; Fig. 1a). In accordance with increased lipolysis at adipose tissue, serum NEFA concentrations increased with duration of fasting (P = 0.02; Fig. 1b). Four hours of fasting maximally decreased serum triacylglycerol concentrations (P < 0.05; Fig. 1c), which remained depressed with additional fasting. The most robust response to fasting was the increase in serum β-OH butyrate concentration (P < 0.0001; Fig. 1d). In fact, serum β-OH butyrate concentration was elevated by 8 h of fasting and continued to increase with duration of fasting. At 16 h of fasting, serum β-OH butyrate was approximately 5 times greater than baseline levels. The relatively steady serum glucose concentrations and elevation in serum β-OH butyrate during a fast result from the shift toward hepatic glucose and ketone body production.Fig. 1


Hepatic adaptations to maintain metabolic homeostasis in response to fasting and refeeding in mice
Changes in serum metabolites in response to fasting duration. Serum concentration of a glucose, b non-esterified fatty acid (NEFA), c triacylglycerol (TAG), and d β-OH Butyrate in mice that were fasted for 0, 4, 8, 12, and 16 h. a,b,c,dBars that do not share a common letter differ significantly (P < 0.05; n = 6)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5037643&req=5

Fig1: Changes in serum metabolites in response to fasting duration. Serum concentration of a glucose, b non-esterified fatty acid (NEFA), c triacylglycerol (TAG), and d β-OH Butyrate in mice that were fasted for 0, 4, 8, 12, and 16 h. a,b,c,dBars that do not share a common letter differ significantly (P < 0.05; n = 6)
Mentions: Fasting decreased serum glucose levels significantly by 12 h (P < 0.05; Fig. 1a). In accordance with increased lipolysis at adipose tissue, serum NEFA concentrations increased with duration of fasting (P = 0.02; Fig. 1b). Four hours of fasting maximally decreased serum triacylglycerol concentrations (P < 0.05; Fig. 1c), which remained depressed with additional fasting. The most robust response to fasting was the increase in serum β-OH butyrate concentration (P < 0.0001; Fig. 1d). In fact, serum β-OH butyrate concentration was elevated by 8 h of fasting and continued to increase with duration of fasting. At 16 h of fasting, serum β-OH butyrate was approximately 5 times greater than baseline levels. The relatively steady serum glucose concentrations and elevation in serum β-OH butyrate during a fast result from the shift toward hepatic glucose and ketone body production.Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

Background: The increased incidence of obesity and associated metabolic diseases has driven research focused on genetically or pharmacologically alleviating metabolic dysfunction. These studies employ a range of fasting-refeeding models including 4&ndash;24&nbsp;h fasts, &ldquo;overnight&rdquo; fasts, or meal feeding. Still, we lack literature that describes the physiologically relevant adaptations that accompany changes in the duration of fasting and re-feeding. Since the liver is central to whole body metabolic homeostasis, we investigated the timing of the fast-induced shift toward glycogenolysis, gluconeogenesis, and ketogenesis and the meal-induced switch toward glycogenesis and away from ketogenesis.

Methods: Twelve to fourteen week old male C57BL/6J mice were fasted for 0, 4, 8, 12, or 16&nbsp;h and sacrificed 4&nbsp;h after lights on. In a second study, designed to understand the response to a meal, we gave fasted mice access to feed for 1 or 2&nbsp;h before sacrifice. We analyzed the data using mixed model analysis of variance.

Results: Fasting initiated robust metabolic shifts, evidenced by changes in serum glucose, non-esterified fatty acids (NEFAs), triacylglycerol, and &beta;-OH butyrate, as well as, liver triacylglycerol, non-esterified fatty acid, and glycogen content. Glycogenolysis is the primary source to maintain serum glucose during the first 8&nbsp;h of fasting, while de novo gluconeogenesis is the primary source thereafter. The increase in serum &beta;-OH butyrate results from increased enzymatic capacity for fatty acid flux through &beta;-oxidation and shunting of acetyl-CoA toward ketone body synthesis (increased CPT1 (Carnitine Palmitoyltransferase 1) and HMGCS2 (3-Hydroxy-3-Methylglutaryl-CoA Synthase 2) expression, respectively). In opposition to the relatively slow metabolic adaptation to fasting, feeding of a meal results in rapid metabolic changes including full depression of serum &beta;-OH butyrate and NEFAs within an hour.

Conclusions: Herein, we provide a detailed description of timing of the metabolic adaptations in response to fasting and re-feeding to inform study design in experiments of metabolic homeostasis. Since fasting and obesity are both characterized by elevated adipose tissue lipolysis, hepatic lipid accumulation, ketogenesis, and gluconeogenesis, understanding the drivers behind the metabolic shift from the fasted to the fed state may provide targets to limit aberrant gluconeogenesis and ketogenesis in obesity.

No MeSH data available.