Energy Homeostasis by the Peripheral Serotonergic System

Energy homeostasis is maintained by balancing energy intake and energy expenditure. In addition to the central nervous system, several hormones play a key role in energy homeostasis in the whole body. In particular, serotonin is regarded as one of the key regulators of energy homeostasis. Serotonin is unique in that it is able to act in both the brain as a neurotransmitter and the peripheral tissue as a gastrointestinal hormone. In the brain, serotonin is thought of as a pharmacological target for anti-obesity treatments because it greatly inhibits meal size and body weight gain. In contrast, serotonin in the periphery has not been targeted as a strategy for anti-obesity treatment, even though almost all of the serotonin produced in the body is produced in the peripheral tissue. Recently, the peripheral serotonergic signal has been shown to regulate glucose and lipid metabolism through autocrine and paracrine signals in energy homeostasis-related tissues, including the pancreatic ? cell, liver, white adipose tissue, brown adipose tissue, and skeletal muscle. Thus, it is possible that the serotonergic system in the peripheral tissue is a new therapeutic target for metabolic disease, including obesity and diabetes. Here, we summarize the role of peripheral serotonin in the regulation of energy homeostasispublishersversio

Menaquinone‐4 Enhances Steroidogenesis in Testis Derived Tumor Cells Via the Elevation of cAMP Level

Naturally existing vitamin K consists of vitamins K1 and K2. Menaquinone‐4 (MK‐4), an analog of vitamin K2 and a product of vitamin K1 metabolism, can be detected in several organs, including the testis; however, the function of MK‐4 in these tissues has not been well characterized. Recent studies have suggested that vitamin K is involved in enhancing protein kinase A (PKA) activity in several cell types, thus regulating numerous PKA‐dependent biological processes. To highlight the effect of vitamin K, we focused on its role in the steroidogenic pathway. Experiments on vitamin K–deficient rats revealed a reduced expression of genes involved in the biosynthesis of cholesterol and steroid hormones in the testis. Moreover, compared with control animals, rats fed on MK‐4 diet presented significantly higher testosterone levels in the plasma and testis. These results suggest that vitamin K is involved in the steroidogenic pathway in the testis. Testosterone levels were found to increase in a dose‐dependent manner also in cell‐based experiments upon addition of MK‐4, but such an effect was not observed in vitamin K1 levels. Furthermore, the effect of MK‐4 on testosterone production was abolished by the specific PKA inhibitor H89, thus confirming the regulatory role of MK‐4 on PKA activation. Here, we describe how MK‐4 modulates PKA activation by enhancing intracellular 3′,5′‐cyclic adenosine monophosphate (cAMP) levels in testis‐derived I‐10 cells. The presented evidence supports the role of MK‐4 in cAMP/PKA signaling and steroidogenesis

Recent Topics in the Studies of Laboratory of Nutrition, Tohoku University : Newly Clarified Function of Vitamin K

Vitamin K (VK) is essential for blood coagulation and bone metabolism in mammals as a Gla-protein activating factor, i.e., VK acts as a cofactor in the posttranslational synthesis of γ-carboxyglutamic acid (Gla) from glutamic acid (Glu) residues in the nascent proteins. Menaquinone-4 (MK-4) is one of the VK_2 analogues, and is well known to have bioactivity in the suppression of bone resorption through apoptosis of osteoclast cells, thus MK-4 is now also used clinically as a therapeutic drug for the osteoporosis. Besides of these well-known functions, MK-4 is strongly presumed to have other novel functions because we have gradually recognized that MK-4 accumulates in various tissues of germfree animals fed an MK-4-free diet. Accordingly, we have focused on clarification of the mechanism of MK-4 formation in several tissues, using both in vitro tissue homogenates (bovine, rats, mice, chicken) and in vivo experiments with rats and mice. To elucidate the biological role of MK-4 production, we used germfree rats to eliminate MK-n synthesized by intestinal flora. Our in vivo results indicate that MK-4 is produced in diverse tissues from ingested vitamin K analogues, including vitamin K_1, MK-n (MK-6, MK-7, and MK-10); and VK_3 without enzymatic participation of microorganisms in the intestine. In addition to the liver and bone, VK is found in the brain, heart, testis, kidney, pancreas and salivary glands mainly as menaquinone-4 (MK-4). However, the physiological role of MK-4 in these various organs has not been fully understood yet. In the present study we identified genes of which expression is changed in testis under vitamin K deficient condition using DNA microarray. The genes involved in the biosynthesis pathway of cholesterol and steroid hormone were decreased in vitamin K deficient group. The amount of Cyp11a (P450scc) mRNA, rate-limiting enzyme for testosterone synthesis, was positively correlated with the concentration of MK-4 in testis. Moreover, the concentration of testosterone in plasma and testis was decreased in vitamin K deficient group compared with the control and vitamin K supplemented groups. These results suggests that vitamin K is involved in steroid production in testis through the regulation of Cyplla

Menaquinone-4 enhances testosterone production in rats and testis-derived tumor cells

<p>Abstract</p> <p>Background</p> <p>Vitamin K is essential for the posttranslational modification of various Gla proteins. Although it is widespread in several organs, including the testis, the function of vitamin K in these organs is not well characterized. In this study, we investigated the function of vitamin K in the testis and analyzed its role in steroidogenesis.</p> <p>Methods</p> <p>Eight-week-old male Wistar rats were fed a diet supplemented with menaquinone-4 (MK-4, 75 mg/kg diet), one of the predominant K₂vitamins present in the testis, for 5 weeks. <it>In vivo </it>testosterone levels of the rats' plasma and testes were measured by enzyme-linked immunosorbent assay, and <it>in vitro </it>testosterone levels of testis-derived tumor cells (I-10 cells) maintained in Ham's F-10 medium with 10% fetal bovine serum were measured following treatment with MK-4 (0 to 100 μM) at several time points. Testosterone and cellular protein levels were analyzed with respect to their effects on steroidogenesis.</p> <p>Results</p> <p>Testosterone levels in the plasma and testes of MK-4-fed rats were significantly increased compared to those of control rats, with no obvious differences in plasma luteinizing hormone levels. Secreted testosterone levels from I-10 cells were elevated by MK-4, but not by vitamin K₁, in a dose-dependent manner independent of cAMP treatment. Western blot analysis revealed that expression of CYP11A, the rate-limiting enzyme in steroidogenesis, and phosphorylation levels of protein kinase A (PKA) and the cAMP response element-binding protein were all stimulated by the presence of MK-4. Enhancement of testosterone production was inhibited by H89, a specific inhibitor of PKA, but not by warfarin, an inhibitor of γ-glutamylcarboxylation.</p> <p>Conclusions</p> <p>MK-4 stimulates testosterone production in rats and testis-derived tumor cells via activation of PKA. MK-4 may be involved in steroidogenesis in the testis, and its supplementation could reverse the downregulation of testosterone production in elders.</p

Serotonin Improves High Fat Diet Induced Obesity in Mice

There are two independent serotonin (5-HT) systems of organization: one in the central nervous system and the other in the periphery. 5-HT affects feeding behavior and obesity in the central nervous system. On the other hand, peripheral 5-HT also may play an important role in obesity, as it has been reported that 5-HT regulates glucose and lipid metabolism. Here we show that the intraperitoneal injection of 5-HT to mice inhibits weight gain, hyperglycemia and insulin resistance and completely prevented the enlargement of intra-abdominal adipocytes without having any effect on food intake when on a high fat diet, but not on a chow diet. 5-HT increased energy expenditure, O2 consumption and CO2 production. This novel metabolic effect of peripheral 5-HT is critically related to a shift in the profile of muscle fiber type from fast/glycolytic to slow/oxidative in soleus muscle. Additionally, 5-HT dramatically induced an increase in the mRNA expression of peroxisome proliferator-activated receptor coactivator 1α (PGC-1α)-b and PGC-1α-c in soleus muscle. The elevation of these gene mRNA expressions by 5-HT injection was inhibited by treatment with 5-HT receptor (5HTR) 2A or 7 antagonists. Our results demonstrate that peripheral 5-HT may play an important role in the relief of obesity and other metabolic disorders by accelerating energy consumption in skeletal muscle

Astrodynamics Science About Itokawa, Gravity and Ephemeris

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/76347/1/AIAA-2006-6658-569.pd

Effects of household-scale cooking on volatile compounds, sensory profile, and hypotensive effect of Kenikir (<i>Cosmos caudatus</i>)

Kenikir (Cosmos caudatus) can be used in the preparation of raw and cooked vegetables in some Indonesian dishes. The cooking process may affect the appearance, chemical properties, and flavor of kenikir. This study aims to determine the effect of household scale cooking on the volatile compounds, sensory profiles, and hypotensive activity of kenikir. Fresh kenikir samples and samples boiled or steamed at 100 ℃ (for 3 and 5 minutes) were analyzed for volatile compounds compositions (solid-phase microextraction-Gas chromatography-mass spectrometry, SPME-GCMS), sensory profiles by free choice profiling, and in-vivo study by using stroke-prone spontaneously hypertensive rats (SHRSP)—a model of spontaneous hypertension. The GCMS analysis identified 30 volatile compounds from 5 compound groups, namely alcohols (2 compounds), benzenes (3 compounds), esters (3 compounds), monoterpenes (10 compounds), and sesquiterpenes (12 compounds). Several compounds, namely (Z)-3-hexenol, α-cadinol, and 3-carene were only detected in fresh kenikir, whereas β-myrcene and β-elemene compounds were only identified after cooking. The principal component analysis of sensory attributes associated fresh kenikir with bright color and minty taste, steamed kenikir with floral aroma, and boiled kenikir with juicy, moist, tender, and smooth texture. Furthermore, a hypotensive effect was shown in the water extract of kenikir after 2 and 4 hours of single oral administration in SHRSP. In summary, the heating process (boiled and steamed) of kenikir has changed its volatile compound composition, which can affect its sensory profiles. In addition, the water extract of kenikir can diminish hypertension in SHRSP