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

Abstract

BackgroundThe 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.MethodsTwelve 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.ResultsFasting 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.ConclusionsHerein, 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.

Segregated hepatocyte proliferation and metabolic states within the regenerating mouse liver

“…At 48 hours, the E‐cadherin staining became more robust while maintaining its periportal pattern, as noted previously after a milder 30% PH protocol . Here, mitotic figures were centered around the interface of the E‐cadherin‐positive and E‐cadherin‐negative regions, consistent with their primarily midlobular position, with both E‐cadherin‐positive and E‐cadherin‐negative hepatocytes displaying mitotic figures.…”

“…A) and thus suggests that these nonproliferating hepatocytes maintain normal functions of the liver. To probe the structural and metabolic states of the nonproliferating hepatocytes further, we respectively examined the staining pattern of (i) the adherens junction component E‐cadherin, which is specific to PV proximal hepatocytes and mimics the pattern of periportal metabolic markers (Fig. A), and (ii) GS, which is specific for pericentral hepatocytes (Fig.…”

Thioesterase Superfamily Member 2 Promotes Hepatic VLDL Secretion by Channeling Fatty Acids Into Triglyceride Biosynthesis

“…However, when FAs are abundant, the Them2/PC‐TP complex functions to promote the synthesis of PC for ER membranes . Taken together, these findings provide a plausible mechanism by which Them2/PC‐TP interactions are modulated in response to nutritional status and may function to (1) sustain PC synthesis and facilitate the lipidation of nascent VLDL particles within the ER when lipid substrates are available, and (2) suppress mTORC1 signaling, leading to reduced CCTα activity and decreased VLDL secretion following more severe nutrient deprivation, potentially contributing to the hepatic steatosis associated with prolonged fasting …”

“…Although increased BAT thermogenesis presumably contributes to improving hepatic metabolism, we have observed that the selective ablation of Them2 in skeletal or cardiac muscle reduces basal blood glucose levels and prevents diet‐induced glucose intolerance . It is also possible that distinct genetic backgrounds of L‐Them2 ‐/‐ compared with Them2 ‐/‐ mice could have contributed to the observed differences …”

Sodium‐glucose cotransporter 2 inhibitors regulate ketone body metabolism via inter‐organ crosstalk

“…In our study, the BHB level in liver tissue in a 16 hours fasting condition was 1.85 nmol/mg, increasing to 2.70 nmol/mg by adding SGLT2i. HMGCS2 is considered a key enzyme whose upregulation is essential to ketogenesis . A previous animal study using C57BL/6J mice reported that hepatic HMGCS2 mRNA levels in 8 and 16 hours fasting conditions were 3‐ and 6‐fold higher, respectively, compared with those in a fed state .…”