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Calorie Restriction Modulates Reproductive Development and Energy Balance in Pre-Pubertal Male Rats.

ABSTRACT: The objective was to determine effects of feed restriction and refeeding on reproductive development and energy balance in pre-pubertal male rats. Sprague Dawley rats (n = 32, 24 days old, ~65 g), were randomly allocated into four treatments (n = 8/treatment): (1) Control (CON, ad libitum feed; (2) Mild Restriction (MR, rats fed 75% of CON consumption); (3) Profound Restriction (PR, 50% of CON consumption); or (4) Refeeding (RF, 50% restriction for 14 days, and then ad libitum for 7 days). Feed restriction delayed reproductive development and decreased energy balance and tissue accretion, with degree of reproductive and metabolic dysfunctions related to restriction severity. In RF rats, refeeding largely restored testis weight, sperm production (per gram and total), plasma IGF-1, leptin and insulin concentrations and energy expenditure, although body composition did not completely recover. On Day 50, more CON and RF rats than PR rats were pubertal (5/6, 4/5 and 1/6, respectively; plasma testosterone >1 ng/mL) with the MR group (4/6) not different. Our hypothesis was supported: nutrient restriction of pre-pubertal rats delayed reproductive development, induced negative energy balance and decreased metabolic hormone concentrations (commensurate with restriction), whereas short-term refeeding after profound restriction largely restored reproductive end points and plasma hormone concentrations, but not body composition.

SUBMITTER: Rizzoto G

PROVIDER: S-EPMC6770304 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Calorie Restriction Modulates Reproductive Development and Energy Balance in Pre-Pubertal Male Rats.

Rizzoto Guilherme G Sekhar Deepa D Thundathil Jacob C JC Chelikani Prasanth K PK Kastelic John P JP

Nutrients 20190823 9

The objective was to determine effects of feed restriction and refeeding on reproductive development and energy balance in pre-pubertal male rats. Sprague Dawley rats (<i>n</i> = 32, 24 days old, ~65 g), were randomly allocated into four treatments (<i>n</i> = 8/treatment): (1) Control (CON, ad libitum feed; (2) Mild Restriction (MR, rats fed 75% of CON consumption); (3) Profound Restriction (PR, 50% of CON consumption); or (4) Refeeding (RF, 50% restriction for 14 days, and then ad libitum for ...[more]

PMID: 31450760

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Project description:ObjectiveCalorie restriction is a first-line treatment for overweight individuals with metabolic impairments. However, few patients can adhere to long-term calorie restriction. An alternative approach to calorie restriction that also causes negative energy balance is mitochondrial uncoupling, which decreases the amount of energy that can be extracted from food. Herein we compare the metabolic effects of calorie restriction with the mitochondrial uncoupler BAM15 in the db/db mouse model of severe hyperglycemia, obesity, hypertriglyceridemia, and fatty liver.MethodsMale db/db mice were treated with ∼50% calorie restriction, BAM15 at two doses of 0.1% and 0.2% (w/w) admixed in diet, or 0.2% BAM15 with time-restricted feeding from 5 weeks of age. Mice were metabolically phenotyped over 4 weeks with assessment of key readouts including body weight, glucose tolerance, and liver steatosis. At termination, liver tissues were analysed by metabolomics and qPCR.ResultsCalorie restriction and high-dose 0.2% BAM15 decreased body weight to a similar extent, but mice treated with BAM15 had far better improvement in glucose control. High-dose BAM15 treatment completely normalized fasting glucose and glucose tolerance to levels similar to lean db/+ control mice. Low-dose 0.1% BAM15 did not affect body mass but partially improved glucose tolerance to a similar degree as 50% calorie restriction. Both calorie restriction and high-dose BAM15 significantly improved hyperglucagonemia and liver and serum triglyceride levels. Combining high-dose BAM15 with time-restricted feeding to match the time that calorie restricted mice were fed resulted in the best metabolic phenotype most similar to lean db/+ controls. BAM15-mediated improvements in glucose control were associated with decreased glucagon levels and decreased expression of enzymes involved in hepatic gluconeogenesis.ConclusionsBAM15 and calorie restriction treatments improved most metabolic disease phenotypes in db/db mice. However, mice fed BAM15 had superior effects on glucose control compared to the calorie restricted group that consumed half as much food. Submaximal dosing with BAM15 demonstrated that its beneficial effects on glucose control are independent of weight loss. These data highlight the potential for mitochondrial uncoupler pharmacotherapies in the treatment of metabolic disease.

Dataset Information

Calorie Restriction Modulates Reproductive Development and Energy Balance in Pre-Pubertal Male Rats.

Publications

Calorie Restriction Modulates Reproductive Development and Energy Balance in Pre-Pubertal Male Rats.

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