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.2008 Jul;22(7):1723-34.
doi: 10.1210/me.2008-0067. Epub 2008 May 1.

Oxytocin deficiency mediates hyperphagic obesity of Sim1 haploinsufficient mice

Affiliations

Oxytocin deficiency mediates hyperphagic obesity of Sim1 haploinsufficient mice

Bassil M Kublaoui et al. Mol Endocrinol.2008 Jul.

Abstract

Single-minded 1 (Sim1) encodes a transcription factor essential for formation of the hypothalamic paraventricular nucleus (PVN). Sim1 haploinsufficiency is associated with hyperphagic obesity and increased linear growth in humans and mice, similar to the phenotype of melanocortin 4 receptor (Mc4r) mutations. PVN neurons in Sim1(+/-) mice are hyporesponsive to the melanocortin agonist melanotan II. PVN neuropeptides oxytocin (Oxt), TRH and CRH inhibit feeding when administered centrally. Consequently, we hypothesized that altered PVN neuropeptide expression mediates the hyperphagia of Sim1(+/-) mice. To test this hypothesis, we measured hypothalamic expression of PVN neuropeptides in Sim1(+/-) and wild-type mice. Oxt mRNA and peptide were decreased by 80% in Sim1(+/-) mice, whereas TRH, CRH, arginine vasopressin (Avp), and somatostatin mRNAs were decreased by 20-40%. Sim1(+/-) mice also showed abnormal regulation of Oxt but not CRH mRNA in response to feeding state. A selective Mc4r agonist activated PVN Oxt neurons in wild-type mice, supporting involvement of these neurons in melanocortin feeding circuits. To test whether Oxt itself regulates feeding, we measured the effects of central administration of an Oxt receptor antagonist or repeated doses of Oxt on food intake of Sim1(+/-) and wild-type mice. Sim1(+/-) mice were hypersensitive to the orexigenic effect of the Oxt receptor antagonist. Oxt decreased the food intake and weight gain of Sim1(+/-) mice at a dose that did not affect wild-type mice. Our results support the importance of Oxt neurons in feeding regulation and suggest that reduced Oxt neuropeptide is one mechanism mediating the hyperphagic obesity of Sim1(+/-) mice.

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Figures

Figure 1
Figure 1
Sim1+/− Mice Exhibit Reduced mRNA Expression of PVN Neuropeptides Real-time PCR showing hypothalamic expression ofSst,CRH,TRH,Avp, andOxt mRNA inSim1+/− mice compared with wild-type mice (n = 5 for each group). Groups were compared using a two-tailed unpairedt test (*,P < 0.05; **,P < 0.01; ***,P < 0.001).Error bars indicatesem. WT, Wild type.
Figure 2
Figure 2
Sim1+/− Mice Exhibit Reduced Expression of PVN Oxt But Not CRH Peptide A, Representative images of immunohistochemical analysis of Oxt and CRH peptides in PVN ofSim1+/− mice compared with wild-type mice (captured with ×10 and ×20 objectives). B, Cell counts and densitometry measurements of Oxt and CRH immunohistochemistry. For B, groups were compared using a two-tailed unpairedt test (*,P < 0.05; **,P < 0.01; ***,P < 0.001).Error bars indicatesem. Numbers of animals are shown in the figure. WT, Wild type.
Figure 3
Figure 3
Sim1+/− Mice Fail to RegulateOxt mRNA Expression in Response to Feeding State Real-time PCR showing hypothalamic expression ofCRH andOxt mRNAs in fed, fasted, and refedSim1+/− micevs. wild-type mice (n = 5 for all groups except wild type fasted andSim1+/− refed, where n = 4). Each subgroup (e.g. wild-type Oxt) was analyzed using one-way ANOVA with Newman-Keuls multiple comparison post-test. (*,P < 0.05 indicates that the fasted group is significantly different from the fed or refed groups). WT, Wild type.
Figure 4
Figure 4
Oxt Is Colocalized with Sim1 in PVN Neurons and PVN Oxt Neurons Are Activated by Central Mc4r-Selective Agonist Injection A, Representative ×40 images showing colocalization of Oxt (red) andSim1-GFP (green). B, Colocalization of Oxt (green) and c-Fos (red) after aCSF or Mc4r-selective agonist (3 μg) icv (×40). After Mc4r-selective agonist treatment, most c-Fos+ neurons in the region shown are Oxt+, and many Oxt+ neurons are c-Fos+ (arrows).
Figure 5
Figure 5
Central Administration of Oxt Receptor Antagonist OVT Exacerbates Hyperphagia ofSim1+/− Mice at a Dose that Does Not Affect Food Intake of Wild-Type Mice After 1 wk of habituation to daily icv injection, mice were injected at the onset of the dark cycle with aCSF on d 1 and 0.5 μg OVT on d 2. OVT food intake was normalized to aCSF food intake for each mouse. Means were calculated for each treatment and compared using a pairedt test (n = 14 for wild-type group; n = 11 forSim1+/− group; ***,P < 0.001). WT, Wild type.
Figure 6
Figure 6
Central Oxt Injection Rescues Hyperphagia and Reduces Weight Gain ofSim1+/− Mice but Does Not Affect Food Intake or Weight Gain of Wild-Type Mice A and B, After 1 wk of habituation to twice daily icv injection, mice were injected twice daily with either aCSF or 10 ng Oxt. Food intake and body weight were measured daily for 12 d. Food intake was analyzed by two-way ANOVA (groupvs. time) and body weight change was analyzed with one-way ANOVA (group). Both analyses were done with a Bonferroni posttest to determine intergroup significance. C, Body weight was measured again and compared with body weight 12 d after the last injection (d 24) on d 12. Groups were compared using one-way ANOVA with a Bonferroni posttest. For A: *,P < 0.05; **,P < 0.01; ***,P < 0.001. For B, and C, groups withdifferent letters are statistically different (P < 0.05). n = 7 for wild-type aCSF; n = 5 forSim1+/− aCSF; n = 7 for wild-type Oxt; n = 8 for Het Oxt. WT, Wild type.
Figure 7
Figure 7
Wild-Type Mice Are Insensitive to High Doses of Intracerebroventricular Oxt but Are Sensitive to the Oxt Receptor Antagonist OVT A, After 1 wk of habituation to daily icv injection, mice were injected at the onset of the dark cycle with either aCSF or 50 ng, 250 ng, or 1 μg of Oxt. Food intake was normalized to aCSF food intake for each mouse. Means were calculated for each treatment, and the groups at each time point were compared using one-way ANOVA (n = 9,P = NS). B, After 1 wk of habituation to daily icv injection, mice were injected at the onset of the dark cycle with aCSF on d 1 and 1.5 μg OVT on d 2. Food intake was normalized to aCSF food intake for each mouse. Means were calculated for each treatment, and the groups at each time point were compared using a pairedt test. (n = 11; *,P < 0.05; **,P < 0.01; ***,P < 0.001).
Figure 8
Figure 8
Model Showing ARC Adiposity Signals,e.g., Leptin Relayed via α-MSH to PVN Parvocellular Oxt/Sim1 Neurons Projecting to the Hindbrain, Where They Are Integrated with Satiety Signals PVN Sim1 neurons may also integrate satiety signals from reciprocal projections from the NTS (not shown) with adiposity signals from the ARC and elsewhere in the brain. POMC, Proopiomelanocortin.
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