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. 2003 May 13;100(10):6216-20.
doi: 10.1073/pnas.1035720100. Epub 2003 Apr 30.

Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake

R Michael Anson  1 , Zhihong Guo, Rafael de Cabo, Titilola Iyun, Michelle Rios, Adrienne Hagepanos, Donald K Ingram, Mark A Lane, Mark P Mattson
Affiliations

Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake

R Michael Anson et al. Proc Natl Acad Sci U S A. .

Abstract

Dietary restriction has been shown to have several health benefits including increased insulin sensitivity, stress resistance, reduced morbidity, and increased life span. The mechanism remains unknown, but the need for a long-term reduction in caloric intake to achieve these benefits has been assumed. We report that when C57BL6 mice are maintained on an intermittent fasting (alternate-day fasting) dietary-restriction regimen their overall food intake is not decreased and their body weight is maintained. Nevertheless, intermittent fasting resulted in beneficial effects that met or exceeded those of caloric restriction including reduced serum glucose and insulin levels and increased resistance of neurons in the brain to excitotoxic stress. Intermittent fasting therefore has beneficial effects on glucose regulation and neuronal resistance to injury in these mice that are independent of caloric intake.

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Figures

Figure 1
Figure 1
Male C57BL/6 mice compensate for periods of fasting by increasing their food intake and gaining weight at rates similar to mice fed AL. Shown are the average daily food intakes (calculated from 14-day intake) (a) and body weights (b) in mice maintained on one of four feeding regimens: AL, IF, PF, and LDF (40% reduction in calories relative to AL-fed). IF body weights are postfeeding values. Values are the mean of measurements made in eight mice per diet group. At the end of the study, body weights and food intakes of the LDF group were significantly lower than the body weights and food intakes of the AL-fed and IF groups (P < 0.001 in each case). Body weights and food intakes of the AL-fed and IF groups were not significantly different.
Figure 2
Figure 2
Effects of IF and LDF on serum glucose, insulin, IGF-1, and β-hydroxybutyrate levels. Serum concentrations of glucose (a), insulin (b), IGF-1 (c), and β-hydroxybutyrate (d) were quantified in mice that had been maintained for 20 weeks on the indicated feeding regimens. Values are the mean and SEM of determinations made in eight mice per group. Statistical comparisons to the AL-fed group are indicated by * and to the PF group by †: * and †, P ≤ 0.05; ** and ††, P ≤ 0.01; *** and †††, P ≤ 0.001.
Figure 3
Figure 3
IF is superior to caloric restriction in protecting hippocampal neurons against excitotoxic injury. Mice that had been maintained for 20 weeks on the indicated diets were subjected to an intrahippocampal injection of the excitotoxin KA; PBS was injected into the contralateral hippocampus of each mouse. Mice were killed 24 h later, coronal brain sections were stained with cresyl violet, and the numbers of undamaged neurons in regions CA3 and CA1 of the hippocampus were quantified. Values are the mean and SD of determinations made in eight mice per group. (a) Representative images showing cresyl violet-stained neurons in KA- and PBS-injected hippocampi of mice from each diet group. (b) Quantification of damage in hippocampi injected with PBS or KA. *, P < 0.01.
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