Relationship between Anaplastic Lymphoma Kinase (ALK) Inhibitors and Epileptic Seizure Disorder: A Post-Marketing Surveillance Study.

INTRODUCTION: ALK has been to be involved in the uptake and regulation of D2R, a G protein-coupled receptor expressed in various brain regions. Therefore, it is crucial to understand the relationship between ALK inhibitors and seizures is an important issue. This study investigated the relationship between ALK inhibitors and seizures. METHODS: This study investigated the relationship between ALK inhibitors and seizures through a disproportionality analysis using the FAERS. The target drugs were the ALK inhibitors crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. The seizures covered were defined HLGT: ''Seizures (incl subtype)'' including HLT: ''Seizures and seizure disorders NEC.'' This study used the IC, a signal score, as a Bayesian statistical method for disproportionality analysis. RESULTS: The signal scores of ''Seizures and seizure disorders NEC'' for each ALK inhibitor were crizotinib (IC: -0.00052, 95%CrI: -0.38-0.27), ceritinib (IC: 1.18, 95%CrI: 0.68-1.54), alectinib (IC: 0.68, 95%CrI: 0.19-1.02), brigatinib (IC: 1.04, 95%CrI: 0.32-1.54), and lorlatinib (IC: 0.82, 95%CrI: 0.11-1.32). On the other hand, ''Generalized tonic-clonic seizures'', ''partial simple seizures NEC, '' ''Absence seizures,'' and ''partial complex seizures'' had no or few reported cases, and no signal was detected. CONCLUSION: To our knowledge, this is the first report to evaluate the relationship between ALK inhibitors and seizures using post-marketing surveillance data. These results suggest that ceritinib, alectinib, brigatinib, and lorlatinib, which are highly brain-migrating drugs, are associated with seizures.

Association between CDK4/6 inhibitors and drug-related osteonecrosis of the jaw: A pharmacoepidemiological study using the FDA Adverse Events Reporting System.

The most common toxicities associated with cyclin-dependent kinase (CDK) 4/6 inhibitor therapy include decreased leukopenia and neutropenia due to the inhibition of CDK6 of leukocyte and neutrophil precursors in bone marrow. These hematological toxicities are more commonly observed with palbociclib administration than with abemaciclib administration, which is approximately 13 times more selective against CDK4 than CDK6. Thus, even though both successfully inhibit CDK4/6, the side effects of palbociclib and abemaciclib differ due to differences in selectivity. Recent reports have suggested an association between palbociclib and medication-related osteonecrosis of the jaw; however, reports on this association are inconsistent. This study investigated the potential association of palbociclib and abemaciclib with MRONJ using the FAERS. Signals of "Osteonecrosis of jaw" were detected only in females using palbociclib (cROR025: 2.08). Other signals detected included stomatitis-related adverse events with abemaciclib and intraoral soft tissue damage and infection with palbociclib. As previous exploratory studies have reported MRONJ signals for bisphosphonates and denosumab, we calculated the aROR for palbociclib-induced osteonecrosis of the jaw using concomitant bisphosphonates and denosumab as covariates. A signal was detected even after adjusting for sex, age, and concomitant medications as covariates (aROR0025: 5.74). A proper understanding of the differences in CDK selectivity is necessary for the appropriate use of CDK4/6 inhibitors. To the best of our knowledge, this is the first report on CDK4/6 inhibitors and drug-related osteonecrosis of the jaw. We believe that these results will offer new insights into adverse events related to the use of CDK4/6 inhibitors, and may aid in the proper use of CDK4/6 inhibitors.

Pituitary-Related Adverse Events and Onset Patterns Caused by Immune Checkpoint Inhibitors: Analysis Using the Japanese Adverse Drug Event Report Database.

Background and Objectives: One type of immune-related adverse event caused by immune checkpoint inhibitors (ICIs) is pituitary-related adverse events. The management of pituitary-related adverse events is important because they can be fatal if not treated promptly. Therefore, this study was conducted to investigate the onset of pituitary-related adverse events using the Japanese Adverse Drug Report (JADER) database. Materials and Methods: Cases registered in the JADER database from 2004 to 2019 were used. The target drugs were ipilimumab, nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab, and the target adverse events were the high-level terms "Anterior pituitary hypofunction," "Anterior pituitary hyperfunction," "Posterior pituitary disorder," and "Pituitary neoplasm" in the Medical Dictionary for Regulatory Activities, Japanese version (MedDRA/J). The information component (IC) was used for signal detection and IC delta (ICΔ) was used for women-related signals. Onset timing and patterns were analyzed using the Weibull distribution. Results: Signals were detected with ipilimumab, nivolumab, pembrolizumab, and atezolizumab in "Anterior pituitary hypofunction," with ICs and 95% credible intervals (95%CrI) of 5.53 (5.30-5.69), 4.96 (4.79-5.08), 4.04 (3.76-4.25), and 2.40 (1.53-3.00). Significant signals were detected in women, except for atezolizumab. Additionally, the time of onset was classified as the wear-out failure type. Inverse signals were detected with ipilimumab and nivolumab in "Posterior pituitary disorder," with ICs (95%CrI) of -1.24 (-2.80--0.26), and -0.89 (-1.64--0.37). Conclusions: Anterior pituitary hypofunction is likely to occur with the long-term administration of ipilimumab, nivolumab, and pembrolizumab. Further investigation is needed to determine the differences in the tendencies to detect signals in the anterior and posterior pituitaries between ipilimumab and nivolumab.

Evaluation of the therapeutic effects and tolerability of modified lenvatinib administration methods for unresectable hepatocellular carcinoma: A preliminary study.

Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor, is a standard therapeutic agent for hepatocellular carcinoma, but the high incidence of adverse events (AEs) related to LEN treatment often necessitates treatment discontinuation. The present study aimed to clarify the therapeutic efficacy and tolerability of modified LEN dosing methods, such as alternate-day dosing, necessitated by AEs of LEN. A total of 66 patients who received LEN at Ogaki Municipal Hospital (Ogaki, Japan) between April 2018 and January 2022 were retrospectively evaluated. These patients were divided into those who completed treatment with the standard administration method (standard LEN, n=48) and those who changed from the standard administration method to a modified administration method in the middle of treatment [modified LEN (weekends off/alternate days), n=18]. The treatment duration and reasons for discontinuation of LEN treatment were analysed. The discontinuation rate due to AEs in the modified LEN group (1 patient) was less compared with that in the standard LEN group (16 patients) (P=0.022). The median treatment duration for patients in the standard LEN (n=48), modified LEN (weekends off, n=6) and modified LEN (alternate days, n=12) groups was 71 [95% confidence interval (CI) 55-134], 483 (95% CI: 193-644) and 222 (95% CI: 98-303) days, respectively (P=0.044). Modification of the administration method ensured fewer AE-related treatment discontinuations. However, weekends off dosing showed a longer treatment duration compared with standard dosing, whereas alternate day dosing showed no difference from standard dosing.

Analysis of adverse events leading to dose reduction/interruption of lenvatinib treatment in patients with Child-Pugh B unresectable hepatocellular carcinoma.

INTRODUCTION: We aimed to compare the safety of lenvatinib as first-line treatment for unresectable hepatocellular carcinoma (HCC) in patients with Child-Pugh A (CP-A) and Child-Pugh B (CP-B) and to determine the adverse events (AEs) that cause dose reduction/interruption of treatment in patients with CP-B. METHODS: Sixty-six patients with lenvatinib as a first-line treatment for HCC at Ogaki Municipal Hospital (Ogaki, Japan) between April 2018 and January 2022 were retrospectively evaluated. We analyzed the treatment duration, AEs, and reasons for dose reduction/interruption associated with lenvatinib treatment in patients with CP-A and CP-B HCC. RESULTS: The CP-B group had significantly more cases of grade ≥ 2 fatigue and anorexia than the CP-A group (p = 0.045 and p = 0.042, respectively). Regarding AEs that caused dose reduction/interruption of treatment, the CP-A group had significantly more cases of proteinuria than the CP-B group (p = 0.015), whereas the CP-B group had significantly more cases of hand-foot syndrome (HFS) than the CP-A group (p = 0.013). CONCLUSION: Patients with CP-B have greater difficulty than patients with CP-A in continuing treatment with repeated dose reductions/interruption of treatment due to intolerable grade ≥ 2 AEs (fatigue and anorexia). HFS is more likely to cause dose reduction/interruption of treatment in CP-B than in CP-A unresectable HCC.

[Investigation of Factors Related to Overall Survival in Patients Treated with Gemcitabine plus Paclitaxel(Albumin Suspension)for Advanced or Recurrent Pancreatic Cancer].

In cancer chemotherapy, identifying factors that may affect overall survival is clinically beneficial. In this study, we examined the factors associated with overall survival in patients treated with gemcitabine plus paclitaxel(albumin suspension) (GN)for pancreatic cancer. We included 91 pancreatic cancer patients who underwent GN therapy as the first-line treatment from January 2015-November 2021. In addition to survival from the start of therapy, the factors surveyed were patient background(gender, age, BMI, etc), dose at the start of treatment, baseline laboratory values, presence or absence of neutrophil count reduction, and modified Glasgow Prognostic Score(mGPS). Multivariate analysis showed that a neutrophil count reduction of Grade 3 or higher(p=0.004)and mGPS≤1(p=0.004)significantly increased overall survival. Consequently, 54.9% of patients(50/91)showed a neutrophil count reduction of Grade 3 or higher, and 35.2% of patients (32/91)showed expression of the first course. The study suggests that neutrophil count reduction of Grade 3 or higher and mGPS≤1 are indicators of prolonged overall survival. In particular, neutrophil count reduction had a high incidence in the first course; therefore, appropriate management is required from early stages of treatment. In addition, nutritional support care should be considered prior to starting treatment.

[Incidence of Immune-Related Adverse Events after Switching from a Conventional Regimen of Nivolumab and Pembrolizumab to the Extended Dosing Interval Regimen].

A new nivolumab and pembrolizumab monotherapy regimen with double the conventional dose and longer dosing intervals( the new regimen)has been approved. Here, we report the incidence of immune-related adverse events(irAEs)in the early phase of switching from the conventional regimen to the new regimen at Ogaki Municipal Hospital. Thirty-seven patients switched to the new regimen between October 2020 and February 2021: 7(18.9%)switched to nivolumab and 5 (14.3%)to pembrolizumab. Two of the 7 patients treated with nivolumab developed irAEs. One patient developed Grade 3 colitis on day 51 following the switch to the new regimen, and the treatment was discontinued. The other patient developed Grade 3 adrenal insufficiency on day 72 and was hospitalized. No irAEs were observed with pembrolizumab treatment. These results suggest that high-severity grade irAEs may occur early after switching to the new regimen.

Influence of Dry Eye Disease on the Measurement Repeatability of Corneal Curvature Radius and Axial Length in Patients with Cataract.

The influence of dry eye disease (DED) on ocular biometric measurements is unclear. We aimed to investigate the effect of DED on the repeatability of ocular biometric measurements in cataract patients. Overall, 114 eyes scheduled for cataract surgery were enrolled. Before surgery, DED parameters including tear film break-up time (BUT), corneal and conjunctival staining scores, and subjective symptoms were examined. Corneal curvature radius and axial length were assessed twice on the same day using IOLMaster-500 (Carl Zeiss Meditec), and the absolute difference between the two measurements was calculated and used as an index of measurement repeatability. The measurement repeatability of the steep meridian of corneal curvature radius was significantly worse in eyes with DED than in those without DED (p = 0.044) and was significantly associated with BUT (r = -0.206, p = 0.031). The measurement repeatability of axial length was negatively correlated with BUT (r = -0.199, p = 0.041) and positively correlated with the corneal staining score (r = 0.253, p = 0.009). In conclusion, the measurement repeatability of corneal curvature radius declined in eyes with DED. Shortened BUTs were associated with a deterioration in the measurement repeatability of corneal curvature radius and axial length.

The Effect of Diquafosol Ophthalmic Solution on Clinical Parameters and Visual Function in Soft Contact Lens-Related Dry Eye.

INTRODUCTION: This study evaluated the efficacy and safety of diquafosol ophthalmic solution (DQS) in soft contact lens (SCL)-related dry eye using artificial tear as a control. METHODS: This study enrolled 26 patients with SCL-related dry eye. DQS and artificial tears (AT) were instilled into the right and left eyes, respectively, with their SCLs on. Dry eye examinations (including tear film breakup time, tear volume, and staining score) were performed and visual function (including contrast sensitivity) was also evaluated before (at baseline) and after treatment (at 4- and 8-week examinations). Subjective symptoms were assessed separately in each eye using a questionnaire on dry eye in contact lens wearers. The results were compared before and after treatment, and between the right eyes treated with DQS (the DQS eye) and the left eyes treated with AT (the AT eye) using the mixed effect model. RESULTS: Corneal and conjunctival staining scores at 8-week examination were significantly lower than those at baseline in the DQS eye (p = 0.03; p < 0.001, respectively), but no significant changes were observed in the AT eye. Most subjective symptoms improved significantly in both the DQS and AT eyes. However, major subjective symptoms (dryness and blurry vision) improved significantly only in the DQS eye at 8-week examination. Contrast sensitivity at 8-week examination in the DQS eye improved significantly at 12 cycles/degree compared to baseline (p = 0.001) and was significantly better than that in the AT eye (p = 0.03). There were no adverse events related to DQS or AT. CONCLUSIONS: DQS was effective and safe for SCL-related dry eye. DQS also improved contrast sensitivity. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), Identification No. UMIN000024064.

Microinjection of Reelin into the mPFC prevents MK-801-induced recognition memory impairment in mice.

Reelin, a large extracellular matrix protein, helps to regulate neuronal plasticity and cognitive function. Several studies have shown that Reelin dysfunction, resulting from factors such as mutations in gene RELN or low Reelin expression, is associated with schizophrenia (SCZ). We previously reported that microinjection of Reelin into cerebral ventricle prevents phencyclidine-induced cognitive and sensory-motor gating deficits. However, it remains unclear whether and how Reelin ameliorates behavioral abnormalities in the animal model of SCZ. In the present study, we evaluated the effect of recombinant Reelin microinjection into the medial prefrontal cortex (mPFC) on abnormal behaviors induced by MK-801, an N-methyl-D-aspartate receptor antagonist. Microinjection of Reelin into the mPFC prevented impairment of recognition memory of MK-801-treated mice in the novel object recognition test (NORT). On the other hand, the same treatment had no effect on deficits in sensory-motor gating and short-term memory in the pre-pulse inhibition and Y-maze tests, respectively. To establish the neural substrates that respond to Reelin, the number of c-Fos-positive cells in the mPFC was determined. A significant increase in c-Fos-positive cells in the mPFC of MK-801-treated mice was observed when compared with saline-treated mice, and this change was suppressed by microinjection of Reelin into the mPFC. A K2360/2467A Reelin that cannot bind to its receptor failed to ameliorate MK-801-induced cognitive deficits in NORT. These results suggest that Reelin prevents MK-801-induced recognition memory impairment by acting on its receptors to suppress neural activity in the mPFC of mice.

Distribution of corneal spherical aberration in a Tanzanian population.

PURPOSE: To investigate the distribution of corneal spherical aberration (SA) in Tanzanian people of African descent, and to examine the correlation between corneal SA and ocular parameters. DESIGN: Cross-sectional population-based study. METHODS: Residents aged 40 years and older in three villages in the Mkuranga district in Tanzania were enlisted as study participants. Corneal higher-order aberrations (HOAs) for the right eye were measured with a wavefront analyzer (KR-1W, Topcon) and calculated for the central 6.0-mm zone. Corneal curvature radius (CR), corneal astigmatism, and axial length (AL) were also measured and their correlation with corneal SA was assessed. RESULTS: The right eyes of 657 participants (336 male, 321 female) were analyzed. The mean age of the subjects was 57.2 ± 10.3 years (mean ± SD). The mean corneal SA (Zernike spherical aberration coefficient C40) was 0.188 ± 0.095 µm (-0.242 to 0.613). The SAs in about three-quarters of all subjects were between 0.10 and 0.30 µm. The root mean squares of total corneal HOAs and the third- and fourth-order aberrations were 0.629 ± 0.250 µm, 0.539 ± 0.236 µm, and 0.269 ± 0.110 µm, respectively. Corneal SA showed weak significant correlations with CR (Spearman's rank correlation coefficient, r = -0.177, p < 0.001), corneal astigmatism (r = -0.142, p < 0.001), AL (r = -0.168, p < 0.001), and age (r = -0.085, p < 0.05). CONCLUSIONS: This finding may be beneficial for selecting aspheric intraocular lens in this population.

[Examination of Actual Medical Material Cost and Cost Reduction Related to Exposure Prevention in the Preparation of Anticancer Drugs].

At Ogaki Municipal Hospital, we expanded the preparation of anticancer drugs using a closed system drug transfer device (CSTD)when revising medical fees in 2016. In this study, we investigated the number of regimens and number of preparations for outpatients in December 2017. Subsequently, the cost of all consumables related to the preparation of anticancer drugs was calculated. In total, 574 preparations of 68 regimens were conducted, with CSTD used in the preparation of 331 (57.7%)drugs. The cost associated with preparation of anticancer drugs was 1,608,163 yen/month, of which the CSTD cost was 1,135,315 yen/month(70.6%). Given the disproportionately high cost related to CSTD, we investigated for material cost reduction. Although CSTD has a mechanism for adjusting the differential pressure inside and outside the vial, the conditions were used to calculate medical fee; however, if we use what we do not have, we estimated that the facility burden would be reduced by 24.7%. CSTD can contribute not only to safety through exposure prevention but also to medical cost reduction through introduction of "Drug Vial Optimization." We believe it will continue to act as a medical evidence to reduce medical fee remuneration and ease the conditions of fee calculation.

The incidence and timing of leukocyte overshoot after pegfilgrastim administration.

INTRODUCTION: Pegfilgrastim is a PEGylated formulation of filgrastim with a long half-life. It is highly convenient and less burdensome for patients. However, white blood cell count may temporarily increase after administration; in particular, a leukocyte overshoot may be observed. The present study retrospectively examined the incidence and timing of leukocyte overshoot after pegfilgrastim administration. PATIENTS AND METHODS: Fifty-five patients (118 occasions of pegfilgrastim) were evaluated. Leukocyte overshoot was defined as white blood cell count ≥10,000/mm3 exceeding the reference value. RESULTS: Leukocyte overshoot was observed in 71.2% (84/118) occasions, in 76.4% (42/55) patients. The maximum white blood cell count ≥30,000/mm3 was observed in 30.5% (36/118) occasions in 45.5% (25/55) patients and was observed in 39.3% (33/84) occasions on day 1 after pegfilgrastim administration and 26.2% (22/84) on day 2. Leukocyte overshoot has been observed in only 23.1% (9/39) patients administered with normal granulocyte colony-stimulating factor. However, there were no patients with white blood cell counts ≥30,000/mm3. CONCLUSION: There was a higher frequency of occurrence of leukocyte overshoot in response to pegfilgrastim than in response to normal granulocyte colony-stimulating factor. High incidence of leukocyte overshoot was observed when blood was collected 1-2 days after administration of pegfilgrastim. It is important for patients to understand the characteristics of pegfilgrastim by conducting pharmaceutical guidance.

[Treatment Continuation and Safety of Eribulin for the Treatment of Metastatic Breast Cancer].

The purpose of treatment for patients with metastatic breast cancer is to maintain the patient's quality of life(QOL)with continued treatment for as long as possible.Eribulin was approved in April 2011 for the treatment of metastatic breast cancer, further increasing the selection of therapies available for the management of this disease.The current study presents a retrospective review of 31 patients who received eribulin in our hospital, and analyzes the factors related to the continuation and safety of its use.The median treatment continuation was 114 days(range, 8-281 days), and the treatment involved an average of 5 courses(range, 1-13 courses).There were no significant differences in the continuation of eribulin with regard to the number of previous chemotherapy regimens and modifications undergone by the patients.Neutropenia accounted for 80.6% of adverse eventsBGrade 3; however, the recovery was rapid.The rates of peripheral neuropathy and liver function failures were 12.9% and 6.5%, respectively. These results suggest that eribulin can be continued to be administered with the aim of maintaining QOL, and the therapy can be adjusted according to the patient's situation and the occurrence of adverse events by reducing the dose and treatment delays.

Modulation of brown adipocyte activity by milk by-products: Stimulation of brown adipogenesis by buttermilk.

Brown adipocytes dissipate chemical energy in the form of heat through the expression of mitochondrial uncoupling protein 1 (Ucp1); Ucp1 expression is further upregulated by the stimulation of ß-adrenergic receptors in brown adipocytes. An increase in energy expenditure by activated brown adipocytes potentially contributes to the prevention of or therapeutics for obesity. The present study examined the effects of milk by-products, buttermilk and butter oil, on brown adipogenesis and the function of brown adipocytes. The treatment with buttermilk modulated brown adipogenesis, depending on the product tested; during brown adipogenesis, buttermilk 1 inhibited the differentiation of HB2 brown preadipocytes. In contrast, buttermilk 3 and 5 increased the expression of Ucp1 in the absence of isoproterenol (Iso), a ß-adrenergic receptor agonist, suggesting the stimulation of brown adipogenesis. In addition, the Iso-induced expression of Ucp1 was enhanced by buttermilk 2 and 3. The treatment with buttermilk did not affect the basal or induced expression of Ucp1 by Iso in HB2 brown adipocytes, except for buttermilk 5, which increased the basal expression of Ucp1. Conversely, butter oil did not significantly affect the expression of Ucp1, irrespective of the cell phase of HB2 cells, ie, treatment during brown adipogenesis or of brown adipocytes. The results of the present study indicate that buttermilk is a regulator of brown adipogenesis and suggest its usefulness as a potential food material for antiobesity.

Potential drug interaction between paclitaxel and clopidogrel.

Paclitaxel is mainly inactivated in vivo by cytochrome P5402C8 (CYP2C8). In recent years, the clopidogrel metabolite has been reported to potently inhibit CYP2C8. However, clinical information regarding the interaction between these two drugs is limited. To the best of our knowledge, this is the first retrospective study investigating the potential for the drug interaction between paclitaxel and clopidogrel. A total of 8 cases in which clopidogrel and paclitaxel were used in combination were examined. The incidence of adverse events and discontinuation rate in these cases were assessed. Neutrophil counts were compared in patients prior and subsequent to the combined administration of clopidogrel and paclitaxel. Grade 3 neutropenia occurred in all cases of combination therapy and grade 4 occurred in 7 cases (88%). In addition, 4 cases (50%) showed febrile neutropenia. Four cases (50%) involved a severe adverse event requiring discontinuation of drug administration. In 1 case involving 6 courses of paclitaxel and nedaplatin therapy prior and subsequent to clopidogrel, there was a significant reduction in the average neutrophil count after 8 days of combination treatment (1,240±395 counts/mm3 without clopidogrel; 370±148 counts/mm3 with clopidogrel; mean ± standard deviation, P<0.01). Drug interactions during co-administration of clopidogrel and paclitaxel may cause severe neutropenia. To avoid these interactions, alternative medications should be considered. If these two drugs are used in combination, it may be necessary to monitor for adverse events more carefully.

Effects of vitamin a status on expression of ucp1 and brown/beige adipocyte-related genes in white adipose tissues of beef cattle.

We previously reported the presence of brown/beige adipocytes in the white fat depots of mature cattle. The present study examined the effects of dietary vitamin A on the expression of brown/beige adipocyte-related genes in the white fat depots of fattening cattle. No significant differences were observed in the expression of Ucp1 between vitamin A-deficient cattle and control cattle. However, the expression of the other brown/beige adipocyte-related genes was slightly higher in the mesenteric fat depots of vitamin A-deficient cattle. The present results suggest that a vitamin A deficiency does not markedly affect the expression of Ucp1 in white fat depots, but imply that it may stimulate the emergence of beige adipocytes in the mesenteric fat depots of fattening cattle.

Induction of beige-like adipocytes in 3T3-L1 cells.

There are two types of brown adipocytes: classical brown adipocytes that form the brown fat depots and beige adipocytes that emerge in the white fat depots. Beige adipocytes have a low level of uncoupling protein 1 (Ucp1) expression in the basal state, but Ucp1 expression is increased in response to ß adrenergic receptor activation. The present study explored the factors responsible for the differentiation of 3T3-L1 white preadipocytes to beige adipocytes. Significant expression of Ucp1 was not detected under any tested conditions in the absence of isoproterenol (Iso), an agonist of ß adrenergic receptor. Iso-induced Ucp1 expression was significantly higher in the cells treated with a mixture of triiodothyronine (T3) and 3-isobutyl-1-methylxanthine (IBMX) for days 0-8 than in the control cells. Chronic IBMX treatment was indispensable for the enhanced Iso-induced Ucp1 expression, and treatment with additional rosiglitazone (Rosi) for days 0-8 further increased the Ucp1 expression. Recently, genes were identified that are predominantly expressed in beige adipocytes, which were induced from stromal vascular cells in white fat depots. However, the expression levels of the beige adipocyte-selective genes in the adipocytes induced by the mixture of T3, IBMX and Rosi did not differ from those in the control adipocytes. The present study indicates that 3T3-L1 cells can differentiate to beige-like adipocytes by prolonged treatment with the mixture of T3, IBMX and Rosi and that the gene expression profile of the adipocytes is distinct from those previously induced from white fat depots.

Behavioral palatability of dietary fatty acids correlates with the intracellular calcium ion levels induced by the fatty acids in GPR120-expressing cells.

We recently reported that G-protein-coupled receptor 120 (GPR120) is expressed on taste buds, and that rodents showed preference for long-chain fatty acids (LCFA) at a low concentration. We also showed that the LCFA (1% linoleic acid) increased the extracellular dopamine (DA) level in the nucleus accumbens (NAc), which participates in reward behavior. However, the mechanism underlying the involvement of the GPR120-agonistic activity of LCFA in the palatability of dietary fat remains elusive. Therefore, we examined the association between the GPR120-agonistic activity and palatability of LCFA. First, we measured Ca(2+) signaling in HEK293 cells stably expressing GPR120 under stimulation by various LCFAs. We then assessed the palatability of the various LCFAs by testing the licking behavior in mice and measured the changes in the NAc-DA level by in vivo microdialysis. Consequently, 14- to 22-carbon unsaturated LCFAs showed strong GPR120-agonistic activity. Additionally, mice displayed high licking response to unsaturated 16- and 18-carbon LCFAs, and unsaturated 18-carbon LCFA significantly increased the DA level. The licking rate and the LCFA-dependent increase in DA level also correlated well with the GPR120- agonistic activity. These findings demonstrate that chemoreception of LCFA by GPR120 is involved in the recognition and palatability of dietary fat.