Tamoxifen Improves Glucose Tolerance in a Delivery-, Sex-, and Strain-Dependent Manner in Mice

Abstract

Tamoxifen, a selective estrogen-receptor modulator, is widely used in mouse models to temporally control gene expression but is also known to affect body composition. We report that tamoxifen has significant and sustained effects on glucose tolerance, independent of effects on insulin sensitivity, in mice. IP, but not oral, tamoxifen delivery improved glucose tolerance in three inbred mouse strains. The extent and persistence of tamoxifen-induced effects were sex and strain dependent. These findings highlight the need to revise commonly used tamoxifen-based protocols for gene manipulation in mice by including longer chase periods after injection, oral delivery, and the use of tamoxifen-treated littermate controls.

Figure 1.

IP tamoxifen injections improved glucose tolerance in mice. Data are presented as mean ± SEM unless otherwise indicated. (A) Male and (B) female BALB/cJ mice (n = 5 to 7 mice per sex per condition) had significantly improved glucose tolerance after IP tamoxifen (TMX) administration. (C) Area under the curve for BALB/cJ mice glucose tolerance. (D) Male and (E) female C57BL/6J mice (n = 6 to 9 mice per sex per condition) had significantly improved glucose tolerance after IP TMX administration. (F) Area under the curve for glucose tolerance in C57BL/6J mice glucose tolerance. (G) Glucose tolerance in male 129S1/SvImJ mice (n = 7 male 129S mice per condition) did not change in response to IP TMX administration. (H) TMX-injected female 129S1/SvImJ mice (n = 6 female mice per condition) had significantly improved glucose tolerance. (I) Area under the curve for 129S1/SvImJ mice glucose tolerance. Differences determined by t tests. *P < 0.05; **P < 0.01; ***P < 0.001. Veh, vehicle.

Figure 2.

Persistence of improved glucose tolerance in tamoxifen-injected mice was sex and strain dependent. Data are presented as mean ± SEM unless otherwise indicated. (A) Male and (B) female BALB/cJ mice (n = 5 to 8 mice per sex per condition) retained significantly improved glucose tolerance 3 weeks after IP tamoxifen (TMX) administration. (C) Area under the curve for BALB/cJ glucose tolerance. (D) Male, but not (E) female, C57BL/6J mice (n = 6 to 7 mice per sex per condition) retained significantly improved glucose tolerance 3 weeks after IP TMX administration. (F) Area under the curve for C57BL/6J mice glucose tolerance. (G) Glucose tolerance did not change in male 129S1/SvImJ mice (n = 4 per condition) in response to IP TMX administration. (H) Glucose tolerance in TMX-injected female 129S1/SvImJ mice (n = 4 per condition) was modestly improved 3 weeks after final injection. (I) Area under the curve remained significantly lower for female 129S1/SvImJ mice. Differences determined by t tests. *P < 0.05; **P < 0.01. Veh, vehicle.

Figure 3.

IP tamoxifen (TMX) administration enhanced insulin secretion in male C57BL/6J mice, but insulin sensitivity was unaffected. Data are presented as mean ± SEM unless otherwise indicated. Differences were determined by t tests. (A) GSIS was improved after IP TMX administration in male C57BL/6J mice (n = 5 to 11 mice per condition). (B) GSIS was unchanged by IP TMX administration in female C57BL/6J mice (n = 5 to 8 mice per condition). Insulin sensitivity was unaffected by IP TMX administration in (C) male and (D) female C57BL/6J mice (n = 5 to 6 mice per condition per sex). (E) TMX stimulation significantly increased islet insulin secretion in low-glucose (2.8 mM) conditions (n = 6 vehicle-treated islet cultures and n = 5 TMX-treated islet cultures from six mice). One-sample t test; *P < 0.05. (F) Male TMX-injected C57BL/6J mice (n = 3 to 4 mice per condition) had improved glucose tolerance in response to an oral glucose challenge 1 week after the final TMX injection. (G) Area under the curve for oral glucose tolerance was significantly lower in TMX-injected male C57BL/6J mice. (H) Oral GSIS was improved after IP TMX administration in male C57BL/6J mice (n = 3 to 5 mice per condition). *P < 0.05. Veh, vehicle.

Figure 4.

Oral tamoxifen (TMX) administration did not affect glucose tolerance. Data are presented as mean ± SEM unless otherwise indicated. Glucose tolerance did not change in (A) male and (B) female BALB/cJ mice (n = 4 to 5 mice per sex per condition) in response to TMX diet. (C) Area under the curve for BALB/cJ mice glucose tolerance. Glucose tolerance did not change in (D) male or (E) female C57BL/6J mice (n = 4 to 5 mice per sex per condition) in response to TMX diet. (F) Area under the curve for C57BL/6J mice glucose tolerance. Glucose tolerance did not change in (G) male or (H) female 129S1/SvImJ mice (n = 3 to 5 mice per sex per condition) in response to TMX diet. (I) Area under the curve for 129S1/SvImJ mice glucose tolerance. Veh, vehicle.