Loss of the Par-1b/MARK2 polarity kinase leads to increased metabolic rate, decreased adiposity, and insulin hypersensitivity in vivo
- Jonathan B. Hurova,b,
- Mei Huangc,d,
- Lynn S. Whitea,e,
- Jochen Lennerzf,
- Cheol Soo Choig,
- You-Ree Chog,h,
- Hyo-Jeong Kimg,h,
- Julie L. Priori,
- David Piwnica-Wormsi,j,
- Lewis C. Cantleyk,l,
- Jason K. Kimg,h,
- Gerald I. Shulmane,g, and
- Helen Piwnica-Wormsa,c,e,l
- Departments of aCell Biology and Physiology and
- cInternal Medicine,
- iMolecular Imaging Center, Mallinckrodt Institute of Radiology, and
- Departments of fPathology and Immunology and
- jMolecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110-1093;
- gDepartment of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8020;
- kDivision of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115; and
- eHoward Hughes Medical Institute, Chevy Chase, MD 20815
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Contributed by Lewis C. Cantley, February 8, 2007 (received for review January 2, 2007)
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Fig. 1.Par-1b null mice are growth retarded and have disproportionate reductions in adiposity. (A) Body weights of embryos from 13.5 to 18.5 days postcoitus (d.p.c.) (n = 5–13 per genotype per time point). (B) Body weights of mice from birth to 3 weeks of age (n = 4–19 per genotype per time point). (C) Body weights of Par-1b wild-type (Par-1b+/+, black bars), heterozygous (Par-1b+/−, red bars), or null (Par-1b−/−, gray bars) mice at 1 year of age (n = 7–13 per genotype per sex). (D) Comparison of Par-1b wild-type and null inguinal (I) and epidydymal (E) fat pads. (E) Scatter plot depiction of adiposity in 10- to 12-week-old male Par-1b wild-type and null mice expressed as a ratio of fat mass to body mass as determined by 1H-MRS. Individual mice for each genotype are shown with averages and P value indicated (n = 18–20 per genotype). (F) Hematoxylin and eosin stain of BAT and WAT from Par-1b wild-type and null mice. (Scale bar, 50 μm.) All values are presented as the averages ± standard error. Student's t test was performed for comparisons between groups. P value designations are as follows: ****, P < 0.05; ***, P < 0.01; **, P < 0.005; *, P < 0.001.
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Fig. 2.Par-1b null mice are resistant to weight gain and are hypermetabolic on a high-fat diet. Par-1b wild-type and null males (n = 5 per genotype) were fed a high-fat diet for 16 weeks starting at 3 weeks of age. (A) Body weight of Par-1b wild-type and null mice during the high-fat diet. Averages are plotted ± standard error. All data points represent statistical differences between wild-type and null mice with P < 0.05. In an independent experiment, male Par-1b null (filled bars) and wild-type mice (open bars) (n = 8–12 per genotype) were fed a high-fat diet for 8 weeks, followed by analysis. Par-1b null mice exhibit increased metabolic rate (B), energy expenditure (C), and food intake (D) on a high-fat diet. (E) Respiratory quotient (VCO2/VO2) of Par-1b null mice is not statistically different from wild-type controls. Student t test P values are indicated.
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Fig. 3.Enhanced insulin sensitivity and glucose tolerance in Par-1b null mice. (A) Retro-orbital bleeds were obtained from fed or fasted (12 h) Par-1b+/+ (open bars) and Par-1b−/− (filled bars) mice, and serum insulin levels were measured by RIA (n = 18 mice per genotype). (B) Blood glucose levels were determined for fed or fasted mice (n = 18 mice per genotype). Par-1b+/+ (open bars) and Par-1b−/− (filled bars). (C) Insulin tolerance tests (ITT) were performed by i.p. injection of 0.30 unit/kg insulin into Par-1b+/+ (diamonds) and Par-1b−/− (circles) littermates (n = 14 mice per genotype). Tail bleeds were obtained and glucose levels were monitored at 15-min intervals after insulin injection. Data are plotted as % blood glucose at time 0 before injection. (D) Glucose tolerance tests were performed by intrperitoneal injection of d-glucose at 1 mg/g body weight into Par-1b+/+ and Par-1b−/− littermates (n = 10 mice per genotype). Tail bleeds were obtained, and glucose levels were monitored at 20-min intervals after glucose injection. Data are plotted as % blood glucose at time 0 before injection. Standard error is plotted on the y axis for all values in A–D. Student's t test was performed for comparisons between two groups. P values were as follows: ****, P < 0.05; ***, P < 0.01; **, P < 0.005; *, P < 0.001.
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Fig. 4.microPET analysis of 18F-FDG uptake in Par-1b+/+ and Par-1b−/− mice. Representative coronal section image of Par-1b+/+ and Par-1b−/− mice 1 h after 18F-FDG injection. Par-1b−/− exhibit consistently elevated levels of uptake in intrascapular brown fat (BAT) pads.
Footnotes
- lTo whom correspondence may be addressed. E-mail: lewis_cantley{at}hms.harvard.edu or hpiwnica{at}cellbiology.wustl.edu
- © 2007 by The National Academy of Sciences of the USA
