Hypothalamic TTF-1 orchestrates the sensitivity of leptin.

OBJECTIVE: Thyroid transcription factor-1 (TTF-1), a homeodomain-containing transcription factor, is predominantly expressed in discrete areas of the hypothalamus, which acts as the central unit for the regulation of whole-body energy homeostasis. Current study designed to identify the roles of TTF-1 on the responsiveness of the hypothalamic circuit activity to circulating leptin and the development of obesity linked to the insensitivity of leptin. METHODS: We generated conditional knock-out mice by crossing TTF-1flox/flox mice with leptin receptor (ObRb)Cre or proopiomelanocortin (POMC)Cre transgenic mice to interrogate the contributions of TTF-1 in leptin signaling and activity. Changes of food intake, body weight and energy expenditure were evaluated in standard or high fat diet-treated transgenic mice by using an indirect calorimetry instrument. Molecular mechanism was elucidated with immunohistochemistry, immunoblotting, quantitative PCR, and promoter assays. RESULTS: The selective deletion of TTF-1 gene expression in cells expressing the ObRb or POMC enhanced the anorexigenic effects of leptin as well as the leptin-induced phosphorylation of STAT3. We further determined that TTF-1 inhibited the transcriptional activity of the ObRb gene. In line with these findings, the selective deletion of the TTF-1 gene in ObRb-positive cells led to protective effects against diet-induced obesity via the amelioration of leptin resistance. CONCLUSIONS: Collectively, these results suggest that hypothalamic TTF-1 participates in the development of obesity as a molecular component involved in the regulation of cellular leptin signaling and activity. Thus, TTF-1 may represent a therapeutic target for the treatment, prevention, and control of obesity.

Improvement of pentylenetetrazol-induced learning deficits by valproic acid in the adult zebrafish.

Pentylenetetrazol (PTZ) has been shown to induce seizure-like behavior, learning deficits in passive avoidance response test, and an increase in hsp70 (heat shock protein 70) mRNA expression in the adult zebrafish; PTZ has been increasingly appreciated as an excellent model system for the study of seizures. In this study, we demonstrate that valproic acid (VPA), an antiepileptic drug, suppresses seizure-like behavior and improves learning ability in adult zebrafish treated with PTZ. Pretreatment with VPA significantly reduces rapid involuntary movement and abrupt changes in moving direction in the PTZ-treated zebrafish. PTZ-induced learning impairments were also improved in the zebrafish pretreated with 200 or 500 microM VPA. However, the scopolamine-induced impairments of learning ability were not improved by VPA pretreatment. It is worth noting that while the zebrafish treated with 500 microM VPA for 1-3 weeks learned the passive avoidance response, those treated with 1 or 2mM VPA for 3h didn't. Furthermore, the increased level of hsp70 expression induced by PTZ, a stress marker protein, was significantly reduced in the VPA-pretreated zebrafish brains. Collectively, our data show the antiepileptic effects of VPA in the adult zebrafish, which coincides with reduced hsp70 mRNA expression, rescued learning impairment under PTZ-treated conditions.

Carbachol induces a form of long-term potentiation in lateral amygdala.

We examined the effects of carbachol, a muscarinic acetylcholine receptor agonist, on excitatory synaptic transmission at thalamo-amygdala synapses in rat brain slices. The application of a low concentration of carbachol (0.25 microM) produced a form of long-term potentiation (cLTP) and a transient suppression of synaptic responses, which was blocked by a muscarinic receptor antagonist, atropine (10 microM). M2 receptor agonist produced only a transient suppression, whereas M1 receptor agonist induced both a transient suppression and a long-term potentiation. Induction of cLTP required simultaneous low-frequency afferent stimulation, and was also dependent upon the activation of NMDA receptors. SQ22536 (50 microM), an adenylyl cyclase inhibitor completely blocked cLTP. Consistently, pretreatment with a maximal concentration of forskolin (10 microM) reduced cLTP.

Induction mechanisms for L-LTP at thalamic input synapses to the lateral amygdala: requirement of mGluR5 activation.

L-LTP (late-phase long-term potentiation) at thalamo-amygdala synapses is thought to be critical for auditory fear conditioning, but it has not been clear what kinds of surface receptors and channels are involved in the induction phase of the L-LTP. Here we report that the NMDA receptor antagonist D-AP5 (50 microM), the L-type calcium channel antagonist nifedipine (30 microM) and the metabotropic glutamate receptor 5 antagonist MPEP (10 microM) prevented L-LTP induction when each antagonist was separately applied at saturating concentrations before and during repeated tetanus. By contrast, the mGluR1 antagonist CPCCOEt (80 microM) failed to show any effects on L-LTP induction. Neither D-AP5 nor MPEP produced any significant effects on potentiated synaptic responses when applied after L-LTP had been established. Thus, our data suggest that NMDA receptors, L-type calcium channels and mGluR5 are involved in L-LTP induction in the thalamo-amygdala pathway.