LOD scores for linkage for FST_FLX.

<p>The solid red line at LOD  = 3.33 and the blue dashed line at LOD  = 4.68 denote the genome-wide significance threshold for FST_FLX (SIM) and FST_FLX (CIM), respectively. The gray zone indicates the 2-LOD confidence interval. FST: forced swim test; FST_FLX: immobility in the mouse FST with fluoxetine treatment; LOD: logarithm of odds; SIM: simple interval mapping; CIM: composite interval mapping.</p

Strain-specific response to fluoxetine in mouse FST.

<p>Immobility time in the FST of B6 (1a), BALB (1b), FVB (1c), DBA (1d) and C3H (1e) mice after administration of different doses of fluoxetine. The FST was conducted 30 minutes after fluoxetine or saline injection (i.p.). “*” denotes a p-value lower than 0.05 compared with the saline group in the post hoc analysis. FST: forced swim test.</p

Mouse single nucleotide polymorphisms (SNPs) that were associated with immobility time in the FST after fluoxetine treatment (FST_FLX).

<p>SD: standard deviation; cM: centi-morgan; LOD: logarithm (base 10) of odds; LOD_(SIM): the LOD scores derived from simple interval mapping; LOD_(CIM): LOD scores derived from composite interval mapping;</p>a<p>The proportion of contribution the genetic polymorphism on the overall variation of the immobility time in FST after fluoxetine treatment.</p>b<p>P-value for one way analysis of variance.</p>c<p>The allele that shows significantly shorter immobility time in FST after fluoxetine treatment than the other allele.</p>d<p>The list of the gene located in 1 mega-bases from the SNP.</p

The association of mouse <i>Zfp326</i> function SNP with FST response to fluoxetine treatment.

<p>Genetic variations in <i>Zfp326</i>, rs33550587 (Asp494Gly) (4a) and rs13473815 (4b), are associated with the mouse response to fluoxetine in the FST. The B6×FVB-F2 mice were grouped according to genotype. * p<0.05; ^#p<0.0001. The digits in the bars represent the number of animals in each group. <i>Zfp326</i>: zinc finger protein 326 gene; SNP: single nucleotide polymorphism; FST: forced swim test.</p

Genotype and allele distribution of <i>ZNF326</i> polymorphisms in the controls, and in the patients with major depressive disorder and their responses to 8-weeks’ antidepressant treatment.

*<p>The P-value in boldface indicates the significance survived after correction for multiple comparisons (adjusted significant threshold with Bonferroni’s procedure: P<0.0125). “#” denotes the p-value obtained from Fisher exact test.</p

Increased fat deposition in <i>Leptin^145E/145E</i> mice.

<p>(<b>A</b>) Fat mass of gonadal (Gon) and inguinal (Ing) WAT and interscapular BAT of <i>Leptin^145E/145E</i> (n = 7∼11) and <i>Leptin^+/+</i> mice (n = 19). **<i>P</i><0.01 and ***<i>P</i><0.001 against <i>Leptin^+/+</i>. Morphology of (<b>B</b>) BAT and (<b>C</b>) gonadal and inguinal WAT from 4-month-old male mice. (<b>D</b>) Distribution of cell size in gonadal (n = 3 each) and inguinal (n = 3 each) WAT of <i>Leptin^145E/145E</i> and <i>Leptin^+/+</i> mice.</p

Severe hyperinsulinemia and insulin resistance in <i>Leptin^145E/145E</i> mice.

<p>(<b>A</b>) Serum glucose and insulin levels during 5-hr fasting of <i>Leptin^145E/145E</i> and <i>Leptin^+/+</i> mice. (<b>B</b>) Serum glucose and insulin levels during glucose tolerance tests in 3-month-old male littermates (n = 5∼9). Impaired insulin sensitivity revealed by (<b>C</b>) IR index and (<b>D</b>) insulin tolerance tests of 3-month-old female <i>Leptin^145E/145E</i> mice (n = 8) compared to <i>Leptin^+/+</i> mice (n = 10). (<b>E</b>) Fasting serum triglyceride (TG, left panel), cholesterol (Chol, middle panel), and free fatty acid (FFA, right panel). (<b>F</b>) Serum levels of adiponectin (left panel) and leptin (right panel) of <i>Leptin^145E/145E</i> and <i>Leptin^+/+</i> mice. Numbers of mice are inside bars. *<i>P</i><0.05, **<i>P</i><0.01, and ***<i>P</i><0.001 against <i>Leptin^+/+</i>.</p

Comparison of tertiary structure of wild-type (V145) and mutant (E145) leptin.

<p>(<b>A</b>) Tertiary structure of human leptin (left panel) from X-ray crystallography, and wild-type (V145, middle panel) and mutant (E145, right panel) mouse leptins by homology modeling. The four-helical bundle (helices A–D) structure with an additional short helical segment E is shown. The N and C termini are indicated. (<b>B</b>) Residue 145 and its adjacent site in wild-type and mutant leptins. The hydrogen bonds between residues are shown as yellow dotted lines. The presented structures were taken from snapshots close to the end of 6 ns simulations.</p

Morbid obesity in <i>Leptin^145E/145E</i> mice.

<p>(<b>A</b>) Increased body weight in <i>Leptin^145E/145E</i> mice compared with their <i>Leptin^145E/+</i> and <i>Leptin^+/+</i> littermates. (<b>B</b>) Growth curves and photograph of male <i>Leptin^145E/145E</i> mice (n = 5) and their <i>Leptin^+/+</i> littermates (n = 9). (<b>C</b>) Body lengths of 4-month-old male <i>Leptin^145E/145E</i> and <i>Leptin^+/+</i> mice. (<b>D</b>) Organ weights from <i>Leptin^145E/145E</i> (n = 11) and <i>Leptin^+/+</i> mice (n = 19). (<b>E</b>) Liver histology of <i>Leptin^145E/145E</i>and <i>Leptin^+/+</i> mice. Numbers of mice are inside bars. **<i>P</i><0.01 and ***<i>P</i><0.001 between two genotypes.</p

Hypothalamus gene expression and leptin sensitivity in <i>Leptin^145E/145E</i> mice.

<p>(<b>A</b>) Expression of genes for neuropeptides, including POMC, NPY and AgRP; and SOCS1, SOCS3, and LEPR in the hypothalamus of <i>Leptin^145E/145E</i> mice (n = 5) compared with their <i>Leptin^145E/+</i> (n = 12) and <i>Leptin^+/+</i> (n = 5) littermates. mRNA amount is expressed relative to the average expression in the hypothalamus of <i>Leptin^+/+</i> mice. Leptin sensitivity in <i>Leptin^145E/145E</i> mice revealed by (<b>B</b>) body weight and (<b>C</b>) daily food intake. <i>Leptin^145E/145E</i> mice (n = 3) and control littermates (including both <i>Leptin^145E/+</i>and <i>Leptin^+/+</i>; n = 3) were injected intraperitoneally twice daily with PBS or leptin (1 mg/kg) for three days. (<b>B</b>) Body weight and (<b>C</b>) average daily food intake during injection period. Day 0 represents the average weight before leptin injection. *<i>P</i><0.05 and **<i>P</i><0.01 between two genotypes/groups. ^#<i>P</i><0.05 against PBS-treated <i>Leptin^145E/145E</i> mice. (<b>D</b>) Interaction between leptin and leptin receptor in the mid brain was examined by coimmunoprecipitation. Brain lysates from <i>Leptin^+/+</i>, <i>Leptin^145E/+</i> and <i>Leptin^145E/145E</i> mice were immunoprecipitated with anti-leptin receptor antibody, and immunoblotted with anti-leptin or anti-leptin receptor antibodies. Each band represents the tissue extract mixed from three mice.</p