(A) Relative expression of Jak2 and related genes in male (M) and female (F) JAK2L and control (Con) adult mice. Values are expressed as mean ± SEM and normalized to male control levels (n = 5 for each group). (B) Serum concentrations of IGF-1 in male and female JAK2L and control mice (n = 5 for each group). (C) Serum concentrations of GH in male and female JAK2L and control mice (n = 5 for each group). (D) Weight in grams of a cohort of male and female JAK2L and control mice over time in days (n = 8–10 for each time point). All values are expressed as mean ± SEM; **P < 0.01, ***P < 0.001.

(A) Normal appearance of the liver of an 8-week-old control mouse. (B) Representative gross appearance of steatotic liver of an 8-week-old JAK2L mouse. (C) Liver weight normalized to body weight is expressed as percent body weight in control and JAK2L mice (n = 5 for each group). (D–G) Images of mouse liver taken using a Nikon Optiphot microscope at ×20 magnification with a Zeiss Axiocam HRc camera. (D) H&E-stained section of control liver. (E) Oil red O–stained section of control liver. (F) H&E-stained section of JAK2L liver. (G) Oil red O–stained section of JAK2L liver. (H) TLC analysis of individual liver extracts of control (lanes 2–6), JAK2L (lanes 8–12), and a 1:10 dilution of JAK2L (lanes 14–18) samples. Premixed sterol esters (SE), TGs, and cholesterol (C) standards are all labeled on the left and were run in the first and last lanes. (I) Quantity of TG in liver extracts from control and JAK2L mice (n = 5 for each group). (J) Quantity of cholesterol (total and sterol esters) in liver extracts from control and JAK2L mice (n = 5 for each group). Male mice were used exclusively in the experiments in this figure. All values are expressed as mean ± SEM. ***P < 0.001.

(A) Appearance of mesenteric and omental fat in control mice. (B) Decreased adiposity in JAK2L mice. The enlarged, pale, yellow liver is also visible. (C) Percent body fat as determined by DXA scanning in control and JAK2L mice (n = 5 for each group). (D) Epididymal fat pad weight of control and JAK2L mice (n = 5 for each group). Male mice were used exclusively in the experiments in this figure. Values are expressed as mean ± SEM. *P < 0.05, ***P < 0.001.

(A) Postnatal weights of male offspring from each of 4 groups from the JAK2L-little intercross (n = 8–10 for each time point). (B) Serum concentrations of IGF-1 in the indicated groups (n = 5 for each group). All comparisons are to Con-Con. (C) Serum concentrations of GH in indicated groups (n = 5 for each group). All comparisons are to Con-JAK2L. (D) Plasma FFA in the indicated groups (n = 5 for each group). All comparisons are to Con-JAK2L. (E) Liver weight normalized to body weight is expressed as percent body weight for the indicated groups (n = 5 for each group). All comparisons are to Con-JAK2L. (F) Quantity of TG in liver extracts from the indicated groups (n = 5 for each group). All comparisons are to Con-JAK2L. Male mice were used exclusively in the experiments in this figure. All values are expressed as mean ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001.

Total palmitate (A) and glycerol (D) content of JAK2L and control livers as determined by direct measurement expressed as μmol/g tissue. Fractional new synthesis of palmitate (B) and glycerol (E) in JAK2L and control livers was assessed after injection of ²H₂O and determination of ²H labeling by mass spectrometry. Absolute amount of new palmitate (C) and glycerol (F) synthesized during the 4-hour labeling period expressed as μmol/g tissue. All values are expressed as mean ± SEM (n = 6–9 for both groups). *P = 0.048, **P = 0.0246, ***P = 0.0024.

Normalized expression of Cd36 (A) and Slc27a genes (B) in livers of male and female JAK2L and control adult mice. Values are derived from Affymetrix Mouse Gene 1.0 ST arrays and are normalized to male control levels (n = 5 for each group). (C) CD36 and actin Western blots. Individual liver samples (n = 3) were incubated with antibodies against CD36 (upper blot) and actin (lower blot). The first lane is molecular weight standards (upper blot, 62 kDa; lower blot, 49 and 38 kDa). Lanes 2 and 3 (labeled CD36) are heart tissue from wild-type and CD36-knockout mice. Lanes 4–6 and 7–9 are liver samples from control and JAK2L mice, respectively. The arrowhead points to the CD36 band. (D) Quantified density (intensity × mm² [int × mm²]) of the CD36 bands from the liver blot in C. (E) Normalized expression of Pparg and Cd36 from livers from each of 4 groups from the JAK2L-little intercross (n = 3–4 for each group). Values are derived from real-time quantitative PCR experiments and are normalized to male control levels. Specific comparisons are indicated. (F) Normalized expression of Cd36 from livers of male control and JAK2L mice after a 2-week treatment with the PPARγ-specific antagonist GW9662 (G) (4 mg/g) or vehicle (V) (n = 5 for each group). (G) Quantity of TG in liver extracts from the mice in F. All values are expressed as mean ± SEM. ^†P = 0.015, **P < 0.01, ***P < 0.001.

Model depicting the effect of deletion of JAK2 from hepatocytes leading to (a) a decrease in IGF-1 and a release of feedback inhibition in the hypothalamus, (b) an increase in concentration of GHRH, (c) an increase in the secretion of GH from the pituitary, leading to (d) an increase in GH signaling in adipocytes and presumed increase in GH-mediated lipolysis and liberation of FFA into the plasma, and finally (e) an increase in expression of CD36 in hepatocytes (as a result of decreased GH signaling) and therefore augmented uptake of the increased levels of plasma FFA and development of FL.