Biomedical subjects

Masaaki Nomura

Publications and source records attributed to Masaaki Nomura.

At least 19 recordsLinked to original sources

PubMed2007

Structure-activity relationship of flavonoids for inhibition of epidermal growth factor-induced transformation of JB6 Cl 41 cells.

We found that quercetin, myricetin, quercetagetin, fisetin, (-)-epigallocatechin gallate (EGCG), and theaflavins, among 24 flavonoids examined, markedly inhibited epidermal growth factor (EGF)-induced cell transformation of mouse epidermal JB6 Cl 41 cells. The six flavonoids suppressed the EGF-induced activation of activator protein 1 (AP-1). In addition, myricetin, quercetagetin, EGCG, and theaflavins directly inhibited EGF-induced phosphatidylinositol 3-kinase (PI3K) activation. The important structural features of flavonoids for cell transformation-inhibitory activity are 3'- and 4'-OH on the B-ring, 3-OH on the C-ring, C2=C3 double bond in the C-ring, and the phenylchromone (C6-C5-C6) skeleton in the flavonols, and the galloyl group in EGCG and theaflavins. Our results provide new insight into possible mechanisms of the anti-carcinogenic effects of flavonoids, and could help to provide a basis for the design of novel cancer chemopreventive agents.

Animals↗

PubMed2007

Overproduction of N(epsilon)-(carboxymethyl)lysine-induced neovascularization in cultured choroidal explant of aged rat.

N(epsilon)-(carboxymethyl)lysine (CML) adduct, a major structure of advanced glycation end product, facilitated production of immature microvessels from choroidal explant cultured in fibrin gel. The present study was investigated an action of endogenous CML adduct on neovascularization of cultured choroidal explants of aged Wistar rats with 9 months of age. The number of microvessels budded from explants was counted under optical microscope and used as an index of in vitro neovascularization. Aged choroidal explants increased the neovascularization in an age-dependent manner. Anti-CML antibody decreased age-facilitated neovascularization as well as CML-human serum albumin (HSA)-facilitated neovascularization. Both the aged explant and CML-HSA-treated explant significantly released vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF) alpha and platelet-derived growth factor (PDGF)-B during the culture period. The release of TNF alpha and PDGF-B was earlier than that of VEGF from the aged explants. The antibodies against these factors decreased the CML-facilitated and age-facilitated neovascularization in the choroidal explants. The inhibitory capacity of anti-TNF alpha antibody was greater than those of anti-VEGF and anti-PDGF-B antibodies. In conclusion, endogenous CML adduct overproduced the neovascularization of the aged choroidal explant. The CML adduct releases TNF alpha which might induce the production and release of VEGF for the abnormal choroidal neovascularization in the patients of age-related macular degeneration.

Age Factors↗

PubMed2006

Site-dependent contributions of P-glycoprotein and CYP3A to cyclosporin A absorption, and effect of dexamethasone in small intestine of mice.

We examined whether the oral bioavailability of cyclosporin A is controlled primarily by P-glycoprotein (P-gp) or CYP3A in the small intestine. In situ loop method was used to evaluate the uptake of cyclosporin A (40nmol) at the upper and lower intestine of wild-type and mdr1a/1b knockout mice treated or not treated with dexamethasone (75mg/kg/day, 7 days, i.p.). Expression of CYP3A mRNA in the control group was higher in the upper than the lower intestine, while that of the multidrug resistance-1a (mdr1a) mRNA was in the opposite order. Dexamethasone administration potently induced CYP3A and mdr1a mRNAs in the lower and upper intestine, respectively. At 45min after cyclosporin A administration into an upper intestinal loop of the control group of wild-type mice, the ratio of residual cyclosporin A to dose did not differ significantly from that of mdr1a/1b knockout mice, whereas in dexamethasone-treated wild-type mice, the residual ratio was increased significantly. The ratio of the cyclosporin A metabolite M17 to cyclosporin A in portal venous blood at an upper intestinal loop of mdr1a/1b knockout mice was much higher than that a lower intestinal loop. The M17/cyclosporin A ratio of portal venous blood at a lower intestinal loop in mdr1a/1b knockout mice was increased significantly by dexamethasone treatment. These results suggest that, under physiological conditions, the oral bioavailability of cyclosporin A is mainly controlled by CYP3A in the upper intestine, rather than liver, but when P-gp is induced by steroid, the intestinal absorption of cyclosporin A may be inhibited.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2006

Phosphodiesterase 4 inhibitor rolipram potentiates the inhibitory effect of calcitonin on osteoclastogenesis.

To assess the combination effect of calcitonin and the phosphodiesterase 4 inhibitor rolipram on osteoclastogenesis, adherent cell-depleted bone marrow cells from mouse tibia and femur (ACD-BMCs), which were cultured in the presence of 25 ng/ml colony-stimulating factor 1 (CSF-1) and 100 ng/ml soluble receptor activator of NF-kappaB ligand (sRANKL), were utilized. Calcitonin inhibited formation of tartrate-resistant acid phosphatase-positive multinucleated cells, as mature osteoclasts, by 70% even at 20 pM, whereas rolipram (10 microM) scarcely affected osteoclast formation; in contrast, the combination of both agents led to significant inhibition of multinucleation and pit formation ability of osteoclasts. The combined administration of calcitonin and rolipram attenuated calcitonin receptor mRNA expression in comparison to treatment with either agent alone, whereas expression of RANK and CSF-1 receptor mRNAs was unchanged. Alone, these agents scarcely elevated intracellular cyclic AMP (cAMP) concentration; however, combination treatment with both agents significantly increased cAMP concentration in osteoclast progenitors and osteoclasts. The combination effect was abolished by H-89, an inhibitor of protein kinase A. It appears that rolipram inhibited hydrolysis of cAMP formed by calcitonin in cells and potentiated the inhibitory effect of calcitonin on osteoclastogenesis. The escape phenomenon following calcitonin treatment may also be prevented by concomitant treatment with the phosphodiesterase 4 inhibitor.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2006

Effects of 1-benzylxanthines on cyclic AMP phosphodiesterase 4 isoenzyme.

Based on our results regarding the structure-activity relationships of alkylxanthines and imidazo[2,1-i]purines as phosphodiesterase 4 (PDE4) inhibitors, we designed new 1-benzylxanthines and investigated their PDE4 inhibitory activities. 3,7-Dihydro-7-acetonyl-1-(2,4-dichlorobenzyl)-3-propyl-1H-purine-2,4-dione (2h) exhibited both more selective and more potent PDE4 inhibitory activity than rolipram and XT-611.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2006

Serum aminotransferase activity as a predictor for estimation of total clearance of hepatically metabolized drugs in rats with acute hepatic failure.

The levels of serum aminotransferase activity, including aspartate aminotransferase (AST), in rats with acute hepatic failure at 24 h after an oral administration of CCl4 (0.01-0.5 ml/kg) were about 15-50 times higher (up to nearly 5000 IU/l) than those of vehicle control rats (about 85 IU/l). The values of total clearance (CL(tot)) of cyclosporin A, doxorubicin, tacrolimus and zonisamide in the CCl4-treated rats were decreased to about 1/2-1/3 of those in control rats. There were good correlations between AST activity and hepatic intrinsic clearance (CL(int)) (r=0.733-0.949) for the above drugs, as well as for chlorzoxazone, caffeine, lidocaine and tolbutamide after the intravenous administration of each drug in rats with acute hepatic failure. However, the slope of the linear regression equation, i.e., the ratio of decrease of CL(int) against increase of AST activity, differed markedly among these drugs. We found that there is a good correlation (r=0.953) between the values of the slope and the CL(int) of normal rats for these drugs, except for caffeine. In summary, the linear regression equation enables us to predict the decrease of CL(tot) in rats with acute hepatic failure to be predicted from the increase in serum AST activity. This approach may be useful as a guide for the dose modification of drugs for patients with acute hepatic failure.

Animals↗

PubMed2006

Development of dosage design of hepatic metabolizing drugs using serum albumin level in chronic hepatic failure.

We have previously reported good correlations among serum aminotransferase (AST) activity, metabolic enzyme activity of CYPs, and total clearance (CL(tot)) of probe drugs in rats with acute hepatic failure induced by CCl4. In this study, we searched for new biochemical indicators that correlate with hepatic function and tried to simulate appropriate drug dosage in chronic hepatic failure. Model rats were prepared by administration of CCl4 (1 ml/kg, s.c., 3 times/week) and used at 48 h after the last administration. Serum albumin concentration was time-dependently decreased and correlated well with 3 major biologic determinants of drug clearance, hepatic blood flow (HBF), intrinsic clearance (CL(int)), and the unbound fraction of drugs in plasma (fp) after intravenous administration of cyclophosphamide, tolbutamide, zonisamide, and chlorzoxazone (as probe drugs for low hepatic extraction) and propranolol and lidocaine (as high-hepatic extraction drugs). By calculating these parameters based on prediction equations by the level of albumin, CL(tot) was obtained. As a result of having evaluated this model using administration of cyclosporin, there was a statistically significant relationship between predicted CL(tot) and observed CL(tot). In conclusion, the value of serum albumin level is a useful parameter that correlates well with chronic hepatic function. We have shown that this quantitative administering design using serum albumin level can predict appropriate dosages of hepatic metabolizing drugs in chronic hepatic failure.

Animals↗

PubMed2005

Contributions of intestinal P-glycoprotein and CYP3A to oral bioavailability of cyclosporin A in mice treated with or without dexamethasone.

The contributions of P-glycoprotein (P-gp) and CYP3A to the oral bioavailability (BA) of cyclosporin A (CyA) were separately evaluated by using wild-type and mdr1a/1b knockout mice treated with dexamethasone (DEX). Mice were treated with DEX (1 or 75 mg/kg/day, i.p.) daily for 7 days, and the blood concentrations of CyA were measured after an i.v. or p.o. dose of CyA (10mg/kg) at 1.5h after the last DEX treatment. The BA values of CyA in wild-type and mdr1a/1b knockout mice were similar, 0.25 and 0.287, respectively. As regards expression of mdr1a and CYP3A mRNAs, expression of mdr1a mRNA was weakest in the duodenum, the main absorption site of CyA, along the whole intestine of wild-type mice, while expression of CYP3A was strongest in the duodenum of both types of mice. After treatment with 1 and 75 mg/kg DEX, the BA values decreased to 43 and 25% of the control in wild-type mice, respectively, and to 89 and 73% of the control in mdr1a/1b knockout mice, respectively. Expression of mdr1a mRNA in duodenum of wild-type mice was potently induced by DEX treatment. The expression of CYP3A mRNA in liver and duodenum of both strains was enhanced only by high-DEX treatment. These results suggest that P-glycoprotein plays only a small role in the absorption of CyA under physiological conditions, but the protein is readily induced by DEX and then functions as a more substantial absorption barrier to CyA than does CYP3A in the intestine.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2005

Effects of rikkunshi-to, a traditional Japanese medicine, on the delay of gastric emptying induced by N(G)-nitro-L-arginine.

We evaluated the effects of Rikkunshi-to and several of its ingredients on the delay of gastric emptying induced by a nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine (L-NNA). After oral administration of L-NNA to rats, the gastric emptying rate at 24 h was decreased from 82.8 +/- 2.4% to 53.3 +/- 5.7%. The decrease of the gastric emptying rate induced by L-NNA treatment was markedly ameliorated by administration of Rikkunshi-to (250 and 500 mg/kg, p.o.) in a dose-dependent manner. To identify the active ingredient of Rikkunshi-to, the components were separated according to polarity, and the effects of the respective fractions on gastric emptying were evaluated. Significant efficacy was found in the water and methanol fractions, but not in the 50% aqueous-methanol fraction. Furthermore, hesperidin (1 - 4.29 mg/kg, p.o.) contained in the methanol fraction and L-arginine (4.5 mg/kg, p.o.) contained in the water fraction ameliorated the decrease in the gastric emptying rate induced by L-NNA treatment. These results suggest that Rikkunshi-to ameliorated abnormalities of NO-mediated gastric functions such as delayed gastric emptying, and hesperidin and L-arginine were identified as two of the active ingredients contributing to the ability of Rikkunshi-to to facilitate gastric emptying.

Administration, Oral↗

PubMed2005

Cremophor EL releases cyclosporin A adsorbed on blood cells and blood vessels, and increases apparent plasma concentration of cyclosporin A.

We examined the influence of cremophor EL (crEL) on the disposition kinetics of CyA in rats. A dose of 10mg/kg of CyA in a volume of 750 microL containing 4.3, 16 or 30% concentration of crEL was intravenously administered over 1 min to rats. The values of distribution volume at the steady-state (Vd(ss)) and total clearance (CL(tot)) of CyA in the presence of increasing amounts of crEL were decreased to about 1/3-1/5 of those with 4.3% crEL, in a crEL concentration-dependent manner. The values of blood to plasma concentration ratio (RBP) and the apparent tissue to plasma concentration ratio (K(p,app)) of CyA with 30% crEL were both only about 1/2 of those of CyA with 4.3% crEL. Next, rats were intravenously given 30% crEL solution at 30 min after an intravenous administration of CyA (10 mg/kg) with 4.3% crEL. Subsequently, the blood and plasma concentrations of CyA rose significantly to 2.4 and 4.7 times those seen when i.v. 30% crEL was not given, respectively. In an in vitro study, we found that the uptake of CyA by red blood cells is inhibited by crEL, and that CyA adsorbed on the inner surface of blood vessels after the administration of CyA is released by crEL. The disposition kinetics of CyA is altered by i.v. administration in combination with the surfactant vehicle crEL, in a crEL concentration-dependent manner.

Adsorption↗

PubMed2005

Inhibition of epidermal growth factor-induced cell transformation and Akt activation by caffeine.

We found that caffeine significantly inhibited epidermal growth factor (EGF)- and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell transformation in the JB6 mouse epidermal cell line. The tumor promoter-induced cell transformation was also blocked by treatment with an adenosine A1 receptor antagonist, 8-phenyltheophylline (8-PTH). Caffeine slightly attenuated activation of EGF-induced activator protein 1 (AP-1) activation, which play important roles in cell transformation, but only at the highest concentration examined (1 mM). Interestingly, pretreatment with caffeine suppressed EGF-induced phosphorylation and activation of Akt and ribosomal p 70 S6 protein kinase (p 70 S 6 K), a target of Akt, without inhibiting phosphatidylinositol 3-kinase (PI 3 K) activation. The inhibition of Akt activation of caffeine was not a result of its adenosine receptor antagonism. Because Akt plays a key role in signal transduction pathways leading to cell proliferation and apoptosis, our results provide novel insight into possible mechanisms of the chemotherapeutic effect of caffeine.

Animals↗

PubMed2005

Inhibition of epidermal growth factor-induced cell transformation by tannins.

The mouse epidermal JB6 cell system is a well developed model for studying tumor promotion, and the JB6 Cl 41 promotion sensitive (P+) cell line, in which transformed colonies are induced by epidermal growth factor (EGF), was used to test the anti-tumor promoting effect of seven tannins and two triterpenoids. We found that six tannins, ellagitannins (compounds 1, 2, 3 and 4) and chromone gallates (compounds 6 and 7), significantly blocked EGF-induced cell transformation in a concentration-dependent manner. The inhibition of cell transformation by the tannins was not due to growth inhibition. The ellagitannins, but not the chromone gallates, significantly attenuated EGF-induced activator protein 1 (AP-1) activation, a transcription factor. Compounds 1 and 3, among the ellagitannins analysed, inhibited the EGF-induced phosphorylation of extracellular-signal regulated protein kinases and p38 kinases, which regulate AP-1 activation. On the other hand, compounds 3 and 4 suppressed EGF-induced phosphatidylinositol 3-kinase (PI3K) activation. In addition, all tannins that blocked cell transformation markedly inhibited EGF-induced activation of Akt, a downstream effector of PI3K. Because signal-transduction pathways, including AP-1 and PI3K pathways, have been focused as prime targets for chemopreventive phytochemicals, our results suggest that inhibition by tannins of EGF-induced neoplastic transformation in JB6 cells is related to blocking of Akt activation, and also attenuation of AP-1 activation for ellagitannins.

Animals↗

PubMed2005

Pharmacokinetic advantage of intraperitoneal injection of docetaxel in the treatment for peritoneal dissemination of cancer in mice.

Intraperitoneal administration of docetaxel has been used to treat peritoneal dissemination of cancer, but its safety has not yet been confirmed. We have compared the pharmacokinetic behaviour of docetaxel after intravenous and intraperitoneal administration in CD-1-nu/nu mice bearing MKN45P, a gastric cancer variant line producing peritoneal dissemination. Docetaxel (8 mg kg(-1)) was intravenously or intraperitoneally injected into the mice and at designated times the drug concentration was measured in plasma, ascites fluid, and abdominal tissues (liver, kidney, intestine and spleen, solid cancer, and suspended free cancer). The pharmacokinetic behaviour of docetaxel was similar in control mice and cancer-bearing mice after administration via either route, except that the transfer of docetaxel from the abdominal cavity to systemic blood (plasma) was slower in cancerbearing mice than in control mice. As expected, the intraperitoneal drug concentration was much higher (approximately 100-fold) and was maintained for a longer time in the intraperitoneal injection group than in the intravenous injection group. The drug concentrations in peritoneal solid cancer tissue and suspended free cancer cells were also significantly higher for a longer time in the intraperitoneal injection group than in the intravenous injection group. The values of the plasma area under concentration-time curves (AUC) were similar for both administration routes. The ratio of AUC ascite/AUC plasma after intraperitoneal administration was higher than after intravenous administration. The drug concentration in abdominal organs after intraperitoneal injection was lower during the first 2 h, then became similar to those after intravenous injection. These results indicated that the intraperitoneal administration of docetaxel for peritoneal dissemination was likely to be an effective treatment method, without causing any increase in systemic toxicity.

Animals↗

PubMed2005

The influence of the sennosides on absorption of glycyrrhetic acid in rats.

In the course of our clinical studies of Kampo medicine (traditional Japanese medicines), we observed the pharmacokinetic interactions between two herbs. When Onpito (TJ-8117, Kampo medicine) containing licorice and rhubarb was administered orally to human subjects, we observed that the AUC(0-lim) and Cmax of glycyrrhetic acid (GA) in plasma were lower than those treated with other Kampo medicines containing licorice. In this study, we demonstrate the pharmacokinetic interactions of GA derived from glycyrrhizinic acid (GL) in licorice and anthraquinones derived from rhubarb. To our knowledge, this is the first report to investigate the pharmacokinetic interactions between two herbs. When GL was orally co-administrated to rats with a non-effective dose of sennoside A having purgative activity, the AUC(0-lim) and Cmax of GA decreased. In addition, sennoside A did not affect the metabolism of GL by the intestinal bacteria in vitro. In the examination using an in situ loop of rat colon, the remaining ratio of GA rose drastically by the co-administration of sennoside A, sennidin A and rhein. Observed inhibition activity of these anthraquinones on GA absorption depended on the concentration of the components added. The maximum inhibition ratio was approximately 75% by rhein, 60% by sennoside A and 25% by sennidin A. We conclude that the decrease of the pharmacokinetic parameters of GA in human plasma observed in the clinical study of TJ-8117 is attributable to an interactive action of absorption from the intestinal tract by anthraquinones contained in or derived from rhubarb.

Animals↗

PubMed2005

Reversal of P-glycoprotein-dependent resistance to vinblastine by newly synthesized bisbenzylisoquinoline alkaloids in mouse leukemia P388 cells.

We examined the ability of partially synthesized new compounds from fangchinoline and tetrandrine to reverse P-glycoprotein (P-gp)-dependent multidrug resistance (MDR) in vitro and in vivo. All compound enhanced the in vitro cyctotoxic effect of vinblastin (VBL) at 0.1 microM as potent as 10 microM verapamil against the resistant cell line P388/ADR. The combination effect tended to be strong by substitution of bulky group, resulting 5,14-dibromotetrandrine (compound #9) showed the strongest effect. Compound #9 increased intracellular VBL accumulation in P388/ADR cells, much stronger than verapamil, as well as cytotoxic combined effect. This mechanism seems to inhibit the function of P-gp, but not the expression of P-gp. In combination with VBL, this compound also synergistically prolonged the life-span of P388/ADR-bearing mice. Bisbenzylisoquinoline alkaloids and their derivatives are possible to be good candidates as modifier of MDR in cancer chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Insulin signaling in adipocytes differentiated from mouse stromal MC3T3-G2/PA6 cells.

The stromal MC3T3-G2/PA6 (PA6) cells from mouse clavaria did not require insulin for differentiation into mature adipose cells, although insulin is well known to play a key role in adipocyte differentiation. Large lipid droplets were observed in the cytoplasm of PA6 cells, and mRNA expression of the adipose specific proteins (aP2, PPARgamma, C/EBPalpha, FAS, GLUT4, leptin, and adiponectin) as differentiation markers appeared or increased clearly in the cells at 8 d after stimulation without insulin. In addition, the glycerol released from the cells (lipolysis) was increased in a concentration-dependent manner by isoproterenol. However, the isoproterenol-induced lipolysis in the cells was not influenced by treatment with insulin, although that was observed in extramedullary adipocytes, 3T3-L1 cells. On the other hand, the 2-deoxy-D-[1-3H]glucose uptake in differentiated PA6 cells also increased by insulin, as shown in other adipose cells. In the cells, insulin induced the phosphorylation of extracellular signal-regulated kinases (Erks), Akt at Ser 473 and ribosomal p70 S6 protein kinase (p70 S6K) at Thr 389, and the insulin-induced 2-deoxy-D-[1-3H]glucose uptake was inhibited by pre-treatment with wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K), or ML-9, an Akt inhibitor. These results suggest that the insulin signal for adipogenesis (lipogenesis) and lipolysis in bone marrow stroma PA6 cells differs from extramedullary adipocytes, such as 3T3-L1 cells.

3T3 Cells↗

PubMed2005

Long-term levothyroxine treatment decreases the oral bioavailability of cyclosporin A by inducing P-glycoprotein in small intestine.

We have noticed that the trough level of blood concentration of cyclosporin A (CyA) tends to be lower in patients receiving long-term oral levothyroxine (LTX) than in patients not receiving LTX. We confirmed this clinical observation in experiments using Wistar rats orally given LTX (8 microg/kg) or saline (control) for 3 weeks, followed by CyA (10 mg/kg). The LTX treatment had little effect on the blood concentrations of CyA after i.v. administration, whereas they were decreased significantly after p.o. administration. After p.o. administration, the value of the area under the blood concentration-time curve from 0 to 24 hr and the bioavailability of CyA in the LTX group were decreased to only about one-fifth and a quarter of those in the control group, respectively. After treatment with LTX, the expression levels of mdr1a, mdr1b and CYP3A2 mRNAs in the duodenum were markedly increased to about twice the control, but in jejunum, ileum and liver the expression levels were little changed. These findings suggest that the absorption of CyA, which occurs mainly from the upper intestine, is reduced as a result of efflux transport via P-glycoprotein induced by LTX. In conclusion, careful monitoring of CyA levels is required in the event of LTX administration to patients receiving immunotherapy with CyA.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Inhibitory mechanism of caffeine on insulin-stimulated glucose uptake in adipose cells.

Caffeine inhibits insulin-induced glucose uptake in rat adipocytes and also decreases insulin sensitivity, including whole-body glucose disposal and glucose uptake in skeletal muscle, during a euglycemic-hyperinsulinemic clamp in human. However, the mechanism by which caffeine decreases the insulin sensitivity is not still clear. We found that pre-treatment with caffeine inhibited the insulin-induced 2-deoxy-D-[1-(3)H]glucose uptake in a concentration-dependent manner in mouse preadipose MC-3T3-G2/PA6 cells differentiated into mature adipose cells. Caffeine also suppressed insulin-induced GLUT4 translocation in the differentiated cells. Although caffeine did not alter insulin-induced activation of PI3K and protein kinase C-zeta (PKCzeta), an isoform of atypical PKC, which is reported to have an important role in insulin-induced GLUT4 translocation, we found that insulin-induced phosphorylation and activation of Akt were blocked by pre-treatment with caffeine. Inhibition of insulin-induced 2-deoxy-D-[1-(3)H]glucose uptake by caffeine was also observed in primary cultured brown adipocytes in a concentration-dependent manner. These results may, in part, explain the ability of caffeine to decrease insulin sensitivity.

Adipocytes↗