The effect of short-term fasting on liver and skeletal muscle lipid, glucose, and energy metabolism in healthy women and men

Abstract

Fasting promotes triglyceride (TG) accumulation in lean tissues of some animals, but the effect in humans is unknown. Additionally, fasting lipolysis is sexually dimorphic in humans, suggesting that lean tissue TG accumulation and metabolism may differ between women and men. This study investigated lean tissue TG content and metabolism in women and men during extended fasting. Liver and muscle TG content were measured by magnetic resonance spectroscopy during a 48-h fast in healthy men and women. Whole-body and hepatic carbohydrate, lipid, and energy metabolism were also evaluated using biochemical, calorimetric, and stable isotope tracer techniques. As expected, postabsorptive plasma fatty acids (FAs) were higher in women than in men but increased more rapidly in men with the onset of early starvation. Concurrently, sexual dimorphism was apparent in lean tissue TG accumulation during the fast, occurring in livers of men but in muscles of women. Despite differences in lean tissue TG distribution, men and women had identical fasting responses in whole-body and hepatic glucose and oxidative metabolism. In conclusion, TG accumulated in livers of men but in muscles of women during extended fasting. This sexual dimorphism was related to differential fasting plasma FA concentrations but not to whole body or hepatic utilization of this substrate.

Figures

Fig. 1.

Change in plasma-free FA and ketone body concentrations with short-term fasting in women and men. Data were analyzed using 2-factor repeated-measures ANOVA and are presented as mean with SEM (gray: women; white: men). A: The average plasma-free FA concentrations over the initial 24 h of fasting were significantly higher among women (P = 0.007). This value was determined by summing all free FA concentration values for a subject over the 24-h period and dividing by the number of measurements. B: Although there was a significant rise in plasma-free FA in both sexes between 20 and 32 h of fasting (P < 0.001), the rate of increase was 4-fold greater in men than in women (P = 0.006). C: There was no significant difference in the average plasma ketone concentrations between women and men during the initial and final 24 h of fasting. D: Each sex exhibited a similar rise in concentration over the fasting period. The average plasma ketone concentration was determined by summing all plasma ketone concentration values for a subject over the 24-h period and dividing by the number of measurements. ** P < 0.01; *** P < 0.001.

Fig. 2.

Relative change in lean tissue TG content with fasting in women and men. Measurements were obtained using a Philips 3.0 Tesla ACHIEVA whole-body MR system and a SENSE torso or knee coil with volume selective spectroscopy (STEAM, 2 × 2 × 2 cm voxel). Data were analyzed using 2-factor repeated-measures ANOVA. A and B: A significant disordinal interaction between sex and duration of fasting for hepatic TG content was encountered (P = 0.047). This was due to a significant increase in hepatic TG content from 4 to 24 h in men (P = 0.043) in conjunction with a tendency for levels in women to decrease (P = 0.092). Further changes in hepatic TG content from 24 to 48 h of fasting were not apparent in women or men. C and D: No significant change in intramyocellular TG content was apparent in either sex from 4 to 24 h of fasting. Intramyocellular TG content exhibited an ordinal interaction between sex and duration of fasting (P < 0.001) from 24 to 48 h due to a significant increase in intramyocellular TGs in women but not in men (P = 0.127). Results were similar when the single apparent outlier among the women was excluded from the analysis. * P < 0.05; *** P < 0.001.

Fig. 3.

Change in hepatic glucose and energy metabolism with fasting. Measurements were obtained using a combination of 2H and 13C (oral and intravenous) stable isotope tracers and NMR spectroscopy. No differences in hepatic metabolic fluxes were observed between men or women, so the data were combined to examine the effect of fasting on these pathways. Data were analyzed using 1-factor repeated-measures ANOVA and are presented as mean with SEM. A: The metabolic pathways studied included hepatic glucose production, composed of glycogenolysis, as well as gluconeogenesis occurring from glycerol, lactate, and amino acids. The techniques used also allowed pathways centered on the TCA cycle to be investigated, including cycle turnover, anaplerosis (PC-PEPCK flux), and pyruvate cycling. B: Endogenous glucose production declined significantly from 24 to 48 h of fasting. This reduction was solely due a decrease in glycogenolysis (white) (P < 0.001). Gluconeogenesis occurring from glycerol (dark gray) as well as lactate/amino acids (light gray) did not change over the fasting period (fractional values [inset] are presented as mean and SD). C: Flux through PC and PEPCK tended to decline from 24 to 48 h of fasting. Nonetheless, the rate of anaplerosis (PC-PEPCK flux) was several-fold higher than the actual rate of gluconeogenesis occurring from OAA (light gray) (day 1: 3.6-fold vs. day 2: 2.6-fold; P = 0.009). The excess production of OAA and PEP was accounted for by pyruvate cycling (dots), a futile cycle usually attributed to pyruvate kinase and malic enzyme activity, with pyruvate returning to the TCA cycle via pyruvate carboxylase. The rate of pyruvate cycling decreased significantly with fasting (P = 0.029), completely accounting for the decrease in anaplerotic flux. D: In contrast with a massive induction of ketones with fasting and in spite of an increase in FA availability as the duration of fasting increased, TCA cycle turnover (black) diminished significantly from 24 to 48 h of fasting. * P < 0.05; *** P < 0.001.