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Tamoxifen Treatment in the Neonatal Period Affects Glucose Homeostasis in Adult Mice in a Sex-Dependent Manner
Judith Estrada-Meza1, Jasmine Videlo1, Clara Bron1
1Université Claude Bernard Lyon 1, Université de Lyon, INSERM UMR-S1213, Lyon, France.
Abstract:
Tamoxifen is a selective estrogen receptor modulator used to activate the CREERT2 recombinase, allowing tissue-specific and temporal control of the somatic mutagenesis to generate transgenic mice. Studies integrating development and metabolism require a genetic modification induced by a neonatal tamoxifen administration. Here, we investigate the effects of a neonatal tamoxifen administration on energy homeostasis in adult male and female C57BL/6J mice. C57BL/6J male and female mouse pups received a single injection of tamoxifen 1 day after birth (NTT) and were fed a high-fat/high-sucrose diet at 6 weeks of age. We measured weight, body composition, glucose and insulin tolerance, basal metabolism, and tibia length and weight in adult mice. The neonatal tamoxifen administration exerted long-term, sex-dependent effects on energy homeostasis. NTT female mice became overweight and developed impaired glucose control in comparison to vehicle-treated littermates. NTT females exhibited 60% increased fat mass, increased food intake, decreased physical activity and energy expenditure, impaired glucose and insulin tolerance, and fasting hyperglycemia and hyperinsulinemia. In contrast, NTT male mice exhibited a modest amelioration of glucose and insulin tolerance and long-term decreased lean mass linked to decreased bone weight. These results suggest that the neonatal tamoxifen administration exerted a marked and sex-dependent influence on adult energy homeostasis and bone weight and must therefore be used with caution for the development of transgenic mouse models regarding studies on energy homeostasis and bone biology.
Insights
Neonatal tamoxifen administration impacts adult energy balance differently in male and female mice. Female mice showed weight gain and impaired glucose control, while males had altered metabolism and bone density.
Area of Science:
- Endocrinology
- Metabolism
- Developmental Biology
Background:
- Tamoxifen (a selective estrogen receptor modulator) activates CREERT2 recombinase for controlled genetic modification in mice.
- Neonatal tamoxifen administration is used to induce genetic modifications crucial for developmental and metabolic studies.
- Understanding the long-term effects of this induction method is vital for accurate research outcomes.
Purpose of the Study:
- To investigate the long-term effects of neonatal tamoxifen administration on energy homeostasis in adult male and female C57BL/6J mice.
- To determine the sex-specific impacts of early-life tamoxifen exposure on metabolic parameters and body composition.
Main Methods:
- C57BL/6J mouse pups received a single neonatal tamoxifen injection (NTT) or vehicle control.
- Mice were fed a high-fat/high-sucrose diet from 6 weeks of age.
- Adult mice underwent assessments of weight, body composition, glucose/insulin tolerance, basal metabolism, and bone parameters (tibia length/weight).
Main Results:
- Neonatal tamoxifen administration induced significant, sex-dependent long-term effects on energy homeostasis.
- NTT female mice exhibited increased adiposity (60% fat mass), impaired glucose and insulin tolerance, reduced physical activity, and altered metabolic rate.
- NTT male mice showed improved glucose/insulin tolerance but decreased lean mass and bone weight.
Conclusions:
- Neonatal tamoxifen administration significantly influences adult energy homeostasis and bone biology in a sex-specific manner.
- Researchers using this method for transgenic mouse models in metabolism or bone studies should exercise caution due to these observed effects.
- The findings highlight the importance of considering the long-term consequences of neonatal tamoxifen exposure in experimental design.
