Research ArticleObesity

Physiological consequences of transient hyperleptinemia during discrete developmental periods on body weight in mice

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Science Translational Medicine  01 Jan 2020:
Vol. 12, Issue 524, eaax6629
DOI: 10.1126/scitranslmed.aax6629
  • Fig. 1 Validation of leptin-overexpressing mice.

    (A) Dose response of 1TG control and 2TG dox-induced leptin (lep)–overexpressing mice to increasing amounts of dox in drinking water. (B) Rapid control of leptin expression with two 24-hour dox exposures in 2TG leptin-overexpressing mice. (C) Dynamic induction of circulating leptin after dox gavage 2TG leptin-overexpressing mice. All values are means ± SEM. Student’s t test, ***P < 0.001.

  • Fig. 2 Dox-induced chronic hyperleptinemia in adult mice (P63 to P203).

    (A) Schematic of the study timeline. (B) Plasma leptin concentrations (Student’s t test at each dox dose). (C) Body weight (two-way RM ANOVA with Fisher’s LSD post hoc analysis; genotype, F1,32 = 0.34, P = 0.56). ns, not significant. (D) Fat mass (two-way RM ANOVA with Fisher’s LSD post hoc analysis; genotype, F1,32 = 0.24, P = 0.63). (E) Lean mass (two-way RM ANOVA with Fisher’s LSD post hoc analysis; genotype, F1,32 = 0.44, P = 0.51). (F) Daily caloric food intake per mouse (left axis; two-way RM ANOVA with Fisher’s LSD post hoc analysis; genotype, F1,8 = 0.0036, P = 0.53) and cumulative food intake (right axis). (G) Daily water intake per mouse (two-way RM ANOVA with Fisher’s LSD post hoc analysis; genotype, F1,8 = 0.18, P = 0.68). (H) Venous whole blood glucose concentration (two-way RM ANOVA with Fisher’s LSD post hoc analysis; genotype, F1,32 = 0.016, P = 0.90) in 1TG controls and 2TG dox-induced leptin-overexpressing mice given dox in 5% sucrose water during 20 weeks of escalating dox exposure. All values are means ± SEM. Red brackets, Student’s t test of the final data point. *P < 0.05, **P < 0.01, ***P < 0.001 by Student’s t test (red) or Fisher’s LSD (black).

  • Fig. 3 Cessation of dox-induced chronic (P63 to P203) hyperleptinemia in adult mice.

    (A) Body weight (mixed-effects model with Fisher’s LSD post hoc analysis; genotype, F1,32 = 0.22, P = 0.88). (B) Fat mass (mixed-effects model with Fisher’s LSD post hoc analysis; genotype, F1,32 = 0.012, P = 0.91). (C) Lean mass (mixed-effects model with Fisher’s LSD post hoc analysis; genotype, F1,32 = 0.37, P = 0.55). (D) Daily caloric food intake (left axis; two-way RM ANOVA with Fisher’s LSD post hoc analysis; genotype, F1,8 = 0.24, P = 0.63) and cumulative food intake (right axis) per mouse after dox was discontinued in 1TG controls and 2TG dox-induced leptin-overexpressing mice. Five weeks after dox, cessation mice were switched from chow to 60% HFD (indicated by brown bar). All values are means ± SEM. Red brackets, Student’s t test of the final data point.

  • Fig. 4 Hyperleptinemia during adolescent period (P22 to P56), followed by 60% HFD ad libitum at 14 weeks.

    (A) Schematic of the study timeline. (B) Circulating leptin concentrations (mixed-effects model with Fisher’s LSD post hoc analysis; genotype, F1,34 = 38.6, P < 0.0001). (C) Daily caloric food intake (left axis; two-way RM ANOVA with Fisher’s LSD post hoc analysis; genotype, F1,10 = 1.27, P = 0.29) and cumulative food intake (right axis). (D) Body weight (two-way RM ANOVA with Fisher’s LSD post hoc analysis; genotype, F1,34 = 1.56, P = 0.22). (E) Fat mass (two-way RM ANOVA with Fisher’s LSD post hoc analysis; genotype, F1,34 = 0.016, P = 0.90). (F) Lean mass (two-way RM ANOVA with Fisher’s LSD post hoc analysis; genotype, F1,34 = 2.67, P = 0.11). (G) Body weight gain (two-way RM ANOVA with Fisher’s LSD post hoc analysis; genotype, F1,34 = 3.01, P = 0.092) of 1TG controls and 2TG dox-induced leptin-overexpressing mice throughout the study. All values are means ± SEM. Red brackets, Student’s t test of the final data point. *P < 0.05, **P < 0.01, ***P < 0.001 by Student’s t test (red) or post hoc Fisher’s LSD (black). BW, body weight.

  • Fig. 5 Hyperleptinemia in male and female mice during postnatal period (P0 to P22), followed by switch from ad libitum chow to 60% HFD at 10 weeks.

    (A) Schematic of the study timeline. (B) Circulating leptin concentrations (mixed-effects model with Fisher’s LSD post hoc analysis; genotype, F1,25 = 67, P < 0.0001). (C) Fat mass (mixed-effects model with Fisher’s LSD post hoc analysis; genotype, F1,25 = 9.4, P < 0.01). (D) Lean mass (mixed-effects model with Fisher’s LSD post hoc analysis; genotype, F1,25 = 0.062, P = 0.44). (E) Body weight (two-way RM ANOVA with Fisher’s LSD post hoc analysis; genotype, F1,25 = 7.0, P < 0.05). (F) Daily caloric food intake (left axis; two-way RM ANOVA with Fisher’s LSD post hoc analysis; genotype, F1,8 = 0.62, P = 0.45) and cumulative food intake (right axis) per mouse. (G) Fold increase in caloric intake after the initiation of HFD feeding (two-way RM ANOVA with Fisher’s LSD post hoc analysis; genotype, F1,8 = 5.0, P = 0.56). (H) Body weight gain (two-way RM ANOVA with Fisher’s LSD post hoc analysis; genotype, F1,25 = 11.27, P < 0.01) of 1TG controls and 2TG dox-induced leptin-overexpressing male (♂) mice throughout the study. (I) Regression of fat mass versus circulating leptin concentrations of male (♂) 1TG and 2TG mice at 28 weeks of age, after 18 weeks of HFD. (J) Plasma leptin concentrations (mixed-effects model with Fisher’s LSD post hoc analysis; genotype, F1,39 = 296.4, P < 0.0001). (K) Body weight (two-way RM ANOVA with Fisher’s LSD post hoc analysis; genotype, F1,39 = 6.74, P < 0.013). (L) Fat mass (mixed-effects model with Fisher’s LSD post hoc analysis; genotype, F1,39 = 6.90, P < 0.05). (M) Lean mass (mixed-effects model with Fisher’s LSD post hoc analysis; genotype, F1,39 = 2.23, P = 0.14). (N) Estimated daily caloric food intake (two-way RM ANOVA with Fisher’s LSD post hoc analysis; genotype, F1,13 = 1.55, P = 0.24) and cumulative food intake per mouse of female (♀) 1TG controls and 2TG dox-induced leptin-overexpressing mice. All values are means ± SEM. Red brackets, Student’s t test of the final data point. *P < 0.05, **P < 0.01, ***P < 0.001 by Student’s t test (red) or post hoc Fisher’s LSD (black).

Supplementary Materials

  • stm.sciencemag.org/cgi/content/full/12/524/eaax6629/DC1

    Materials and Methods

    Fig. S1. Validation of leptin-overexpressing ES cells and leptin-overexpressing mice.

    Fig. S2. Bioactivity of leptin.

    Fig. S3. Circulating leptin concentrations during postnatal dox exposure.

    Fig. S4. Dox-induced chronic hyperleptinemia (P63 to P203) in adult mice with concurrent HFD feeding.

    Fig. S5. Release of adult mice from dox-induced chronic (P63 to P203) hyperleptinemia and HFD feeding.

    Fig. S6. Energy expenditure assessment (indirect calorimetry) at 26 weeks of age in postnatally (P0 to P22) hyperleptinemic female mice after 16 weeks of HFD feeding.

    Data file S1. Primary data file used to generate main figures.

    Data file S2. Primary data file used to generate supplementary figures.

    Reference (74)

  • The PDF file includes:

    • Materials and Methods
    • Fig. S1. Validation of leptin-overexpressing ES cells and leptin-overexpressing mice.
    • Fig. S2. Bioactivity of leptin.
    • Fig. S3. Circulating leptin concentrations during postnatal dox exposure.
    • Fig. S4. Dox-induced chronic hyperleptinemia (P63 to P203) in adult mice with concurrent HFD feeding.
    • Fig. S5. Release of adult mice from dox-induced chronic (P63 to P203) hyperleptinemia and HFD feeding.
    • Fig. S6. Energy expenditure assessment (indirect calorimetry) at 26 weeks of age in postnatally (P0 to P22) hyperleptinemic female mice after 16 weeks of HFD feeding.
    • Legends for data files S1 and S2
    • Reference (74)

    [Download PDF]

    Other Supplementary Material for this manuscript includes the following:

    • Data file S1 (Microsoft Excel format). Primary data file used to generate main figures.
    • Data file S2 (Microsoft Excel format). Primary data file used to generate supplementary figures.

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