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White adipocytes are unique in that they contain large unilocular lipid droplets that occupy most of the cytoplasm. To identify genes involved in the maintenance of mature adipocytes, we expressed dominant-negative PPAR[gamma] in 3T3-L1 cells and performed a microarray screen. The fat-specific protein of 27 kDa (FSP27) was strongly downregulated in this context. FSP27 expression correlated with induction of differentiation in cultured preadipocytes, and the protein localized to lipid droplets in murine white adipocytes in vivo. Ablation of FSP27 in mice resulted in the formation of multilocular lipid droplets in these cells. Furthermore, FSP27-deficient mice were protected from diet-induced obesity and insulin resistance and displayed an increased metabolic rate due to increased mitochondrial biogenesis in white adipose tissue (WAT). Depletion of FSP27 by siRNA in murine cultured white adipocytes resulted in the formation of numerous small lipid droplets, increased lipolysis, and decreased triacylglycerol storage, while expression of FSP27 in COS cells promoted the formation of large lipid droplets. Our results suggest that FSP27 contributes to efficient energy storage in WAT by promoting the formation of unilocular lipid droplets, thereby restricting lipolysis. In addition, we found that the nature of lipid accumulation in WAT appears to be associated with maintenance of energy balance and insulin sensitivity., Introduction Obesity is associated with various complications such as insulin resistance, type 2 diabetes, dyslipidemia, and atherosclerosis (1), (2). It results from an imbalance between energy intake and energy expenditure [...]

We investigated the effect of [3-oxidation inhibition on the fat ingestive behavior of BALB/c mice. Intraperitoneal administration to mice of mereaptoacetate, an inhibitor of fatty acid oxidation, significantly suppressed intake of corn oil but not intake of sucrose solution or laboratory chow. To further examine the effect of mercaptoacetate on the acceptability of corn oil in the oral cavity, we examined short-term licking behavior. Mercapto-acetate significantly and specifically decreased the number of licks of corn oil within a 60-s period but did not affect those of a sucrose solution, a monosodium glutamate solution, or mineral oil. In contrast, the administration of 2-deoxyglucose, an inhibitor of glucose metabolism, did not affect the intake or short-term licking counts of any of the tasted solutions. These findings suggest that fat metabolism is involved in the mechanism underlying the oral acceptance of fat as an energy source. licking behavior; fat; palatability

Transforming growth factor-[beta] (TGF-[beta]), a pleiotropic cytokine, regulates cell proliferation, differentiation, and apoptosis, and plays a key role in development and tissue homeostasis. TGF-[beta] functions as an anti-inflammatory cytokine because it suppresses microglia and B-lymphocyte functions, as well as the production of proinflammatory cytokines. However, we previously demonstrated that the intracisternal administration of TGF-[beta] induces fever like that produced by proinflammatory cytokines. In this study, we investigated the mechanism of TGF-[beta]-induced fever. The intracisternal administration of TGF-[beta] increased body temperature in a dose-dependent manner. Pretreatment with cyclooxygenase-2 (COX-2)-selective inhibitor significantly suppressed TGF[beta]-induced fever. COX-2 is known as one of the rate-limiting enzymes of the [PGE.sub.2] synthesis pathway, suggesting that fever induced by TGF-[beta] is COX-2 and [PGE.sub.2] dependent. TGF-[beta] increased [PGE.sub.2] levels in cerebrospinal fluid and increased the expression of COX-2 in the brain. Double immunostaining of COX-2 and von Willebrand factor (vWF, an endothelial cell marker) revealed that COX-2-expressing cells were mainly endothelial cells. Although not all COX-2-immunoreactive cells express TGF-[beta] receptor, some COX-2-immunoreacrive cells express activin receptor-like kinase-1 (ALK-1, an endothelial cell-specific TGF-[beta] receptor), suggesting that TGF-[beta] directly or indirectly acts on endothelial cells to induce COX-2 expression. These findings suggest a novel function of TGF-[beta] as a proinflammatory cytokine in the central nervous system. prostaglandin [E.sub.2]; body temperature; central nervous system; proinflammatory cytokine; blood vessel

When ambient temperature is decreased in mammals, autonomic and behavioral heat-gain responses occur to maintain their core temperatures. However, what molecules in cutaneous sensory nerve endings mediate cooling-induced responses is unclear. Recently, transient receptor potential melastatin-8 (TRPM8) has been identified in cell bodies of sensory neurons as low-temperature and menthol-activated cation channel. We hypothesized that TRPM8 mediates cooling-induced autonomic and behavioral heat-gain responses. To activate TRPM8 specifically, we applied 1-10% menthol to the skin of whole trunk in mice instead of cooling and measured core temperatures and autonomic and behavioral heat-gain responses. Solvent of menthol (100% ethanol) was used as control. Significant elevation of core temperatures was observed between 20 and 120 min after menthol application. Pretreatment with diclofenac sodium, an antipyretic drug, did not affect this hyperthermia, indicating that the menthol-induced hyperthermia is not fever. Menthol application induced a rise in oxygen consumption, shivering-like muscle activity, tail skin vasoconstriction (autonomic responses), and heat-seeking behavior. All of them are typical heat-gain responses. These results support the hypothesis that TRPM8 mediates cooling-induced autonomic and behavioral heat-gain responses. thermoregulation; transient receptor potential channel(s); metabolism

We have recently reported that inhibition of transforming growth factor (TGF)-[beta] in the brain reduced fat-related energy substrates concentrations in response to exercise. We investigated the relevance between the mobilization of fat-related energy substrates (nonesterified fatty acid and ketone bodies) during exercise and the effects of TGF-[beta] in the brain. Low-intensity exercise was simulated by contraction of the hindlimbs, induced by electrical stimulation at 2 Hz in anesthetized rats (Sim-Ex). As with actual exercise, it was confirmed that mobilization of carbohydrate-related energy substrates (glucose and lactic acid) occurred immediately after the onset of Sim-Ex, and mobilization of fat-related energy substrates followed thereafter. The timing of mobilization of fat-related substrates corresponded to that of the increase in TGF-[3 in cerebrospinal fluid (CSF) in Sim-Ex. The level of TGF-[beta] in CSF significantly increased after 10 min of Sim-Ex and remained elevated until 30 min of Sim-Ex. Intracisternal administration of TGF-[beta] caused rapid mobilization of fat-related energy substrates. Meanwhile, there were no effects on the changes in carbohydrate-related substrates. The levels of catecholamines were slightly elevated after TGF-[beta] administration, and, although not significantly in statistical terms, we consider that at least a part of TGF-[beta] signal was transducted via the sympathetic nervous system because of these increases. These data indicate that TGF-[beta] in the brain is closely related to the mobilization of fat-related energy substrates during low-intensity exercise. We hypothesized that the central nervous system plays a role in the regulation of energy metabolism during low-intensity exercise and this may be mediated by TGF-[beta]. central nervous system; energy metabolism; flux; ketone bodies; nonesterifed fatty acid doi:10.1152/ajpregu.00632.2006

We have previously reported that the concentration of transforming growth factor-[beta] (TGF-[beta]) increases in the cerebrospinal fluid of rats during exercise and that there is an increase in whole body fat oxidation following the intracisternal administration of TGF-[beta]. These results led us to postulate that TGF-[beta] in the brain regulates the enhancement of fatty acid oxidation during exercise. To test this hypothesis, we carried out respiratory gas analysis during treadmill running following the inhibition of TGF-[beta] activity in rat brain by intracisternal administration of anti-TGF-[beta] antibody or SB-431542, an inhibitor of the type 1 TGF-[beta] receptor. We found that each reagent partially blocked the increase in the fatty acid oxidation. We also compared the plasma concentrations of energy substrates in the group administered anti-TGF-[beta] antibody and the control group during running. We found that the plasma concentrations of nonesterified fatty acids and ketone bodies in the group administered anti-TGF-[beta] antibody were lower than in the control group at the end of running. In the same way, we carried out respiratory gas analysis during treadmill running after depressing corticotropin-releasing factor activity in the brain using intracisternal administration of astressin, an inhibitor of the corticotropin-releasing factor receptor. However, there were no significant differences in respiratory exchange ratio or oxygen consumption in moderate running (60% maximum oxygen consumption). These results suggest that brain TGF-[beta] has a role in enhancing fatty acid oxidation during endurance exercise and that this regulation is executed at least partly via the type 1 TGF-[beta] receptor signal transduction system. central nervous system; energy metabolism; respiratory exchange ratio; activin receptor-like kinase 5; corticotropin-releasing factor

We have previously reported that the concentration of transforming growth factor-β (TGF-β) increases in the cerebrospinal fluid of rats during exercise and that there is an increase in whole body fat oxidation following the intracisternal administration of TGF-β. These results led us to postulate that TGF-β in the brain regulates the enhancement of fatty acid oxidation during exercise. To test this hypothesis, we carried out respiratory gas analysis during treadmill running following the inhibition of TGF-β activity in rat brain by intracisternal administration of anti-TGF-β antibody or SB-431542, an inhibitor of the type 1 TGF-β receptor. We found that each reagent partially blocked the increase in the fatty acid oxidation. We also compared the plasma concentrations of energy substrates in the group administered anti-TGF-β antibody and the control group during running. We found that the plasma concentrations of nonesterified fatty acids and ketone bodies in the group administered anti-TGF-β antibody were lower than in the control group at the end of running. In the same way, we carried out respiratory gas analysis during treadmill running after depressing corticotropin-releasing factor activity in the brain using intracisternal administration of astressin, an inhibitor of the corticotropin-releasing factor receptor. However, there were no significant differences in respiratory exchange ratio or oxygen consumption in moderate running (60% maximum oxygen consumption). These results suggest that brain TGF-β has a role in enhancing fatty acid oxidation during endurance exercise and that this regulation is executed at least partly via the type 1 TGF-β receptor signal transduction system. [ABSTRACT FROM AUTHOR]

Although physical exercise is well known to improve glucose metabolism, the underlying molecular mechanisms remain largely unclear. We recently revealed by cDNA microarray analyses that the abundance of heparin-binding epidermal growth factor-like growth factor (HB-EGF), which binds to ErbB family receptors in an autocrine or paracrine manner, increases in skeletal muscle of mice after a single bout of treadmill running. To address physiological relevance of this up-regulation to energy homeostasis, we have here generated and characterized mice with muscle-specific overexpression of HB-EGF (MCK-HBEGF). The transgenic mice exhibited significantly higher respiratory quotients on indirect calorimetry compared with wild-type mice at 18 weeks of age (0.91±0.01 vs. 0.84±0.02, p<0.01), suggesting that they preferentially utilize carbohydrate over fat as energy substrates. The blood glucose level during intraperitoneal glucose tolerance test was lower in MCK-HBEGE In these mice, glucose-lowering effect of exogenously administered insulin was greater; and also, insulin-stimulated glucose uptake by skeletal muscle was markedly increased as determined by euglycaemic-hyperinsulinaemic clamp studies. Notably, MCK-HBEGF maintained relatively normal insulin sensitivity even when challenged with a high-fat diet. The insulin sensitizing effects of HB-EGF were accompanied by both relocation of the glucose transporter Glut4 on plasma membrane and down-regulation of pyruvate dehydrogenase kinase 4 (PDK4) in skeletal muscle, events attributable to elevated Akt activity and subsequent inactivation of FOXO proteins, respectively. Consistent with these in vivo findings, recombinant HB-EGF could activate ErbBs and Akt in cultured myotubes. Together, HB-EGF appears to act as an exercise-inducible insulin sensitizer that facilitates peripheral glucose disposal, and may thus be able to ameliorate metabolic disorders such as type 2 diabetes and impaired glucose tolerance. [ABSTRACT FROM AUTHOR]

Background: It has been reported that cystine and theanine, amino acids related to glutathione synthesis, have immunomodulatory effects, such as suppressing inflammation after strenuous exercise. In this study, we examined the effects of oral administration of cystine and theanine during the perioperative period as a pilot study., Methods: Forty-three cases of distal gastrectomy for cancer conducted in our department were assigned to the cystine and theanine group (CT group) or to the placebo control group (P group), and a randomized, single-blind, parallel-group study was then performed. Cystine (700 mg) and theanine (280 mg) or a placebo was administered to participants for 10 continuous days (4 days before to 5 days after surgery). Changes in pre- and postoperative interleukin (IL)-6, C-reactive protein (CRP), albumin, white blood cell (WBC) count, neutrophil count, total lymphocyte count, resting energy expenditure (REE), and body temperature were compared and examined., Results: Ten patients were excluded, leaving 33 patients in the study. The CT group had significantly lower IL-6 values (postoperative day [POD] 4), CRP levels (POD 7), neutrophil counts (POD 4), and body temperatures (POD 5) than the P group (P < .05). In addition, REE in the P group peaked on day 1 (1.14 ± 0.16 [pre- and postoperative ratio]), whereas the CT group did not show any increase on POD 1 (0.99 ± 0.21, P < .05 vs P group)., Conclusions: This study suggests that oral administration of cystine and theanine during the perioperative period may alleviate postgastrectomy inflammation and promote recovery after surgery.

We studied the physiological and behavioral effects of subchronic intracisternal administration of transforming growth factor-beta (TGF-beta) for 7 days. Subchronic intracisternal administration of TGF-beta significantly inhibited the increase in body weight of rats but did not affect food intake. In the measurement of locomotor activity after the final intracisternal administration on day 7, the total count for 1.5 h increased significantly in the TGF-beta group compared with the vehicle group. However, that for 10 h was not different between both groups. Furthermore, significant elevations in oxygen consumption were observed in the TGF-beta group during both light and dark phase. Subchronic TGF-beta treatment induced a significant decrease in the number of total leukocytes and lymphocytes and the relative weight of the thymus, and a significant increase in brown adipose tissue weight. Corticotropin-releasing factor (CRF) is the primary neuroendocrine factor released in response to stress. Subchronic treatment with CRF, as a positive control, significantly affected body weight, food intake, oxygen consumption, total leukocyte and lymphocyte counts, and thymus and adrenal weight. Subchronic TGF-beta administration partially mimicked the stress responses, implicating a role for TGF-beta in the brain in stress.