OBJECTIVEThe significant roles of brown adipose tissue (BAT) in the regulation of energy expenditure and adiposity are established in small rodents but have been controversial in humans. The objective is to examine the prevalence of metabolically active BAT in healthy adult humans and to clarify the effects of cold exposure and adiposity.RESEARCH DESIGN AND METHODSIn vivo 2-[18F]fluoro-2-deoxyglucose (FDG) uptake into adipose tissue was measured in 56 healthy volunteers (31 male and 25 female subjects) aged 23–65 years by positron emission tomography (PET) combined with X-ray computed tomography (CT).RESULTSWhen exposed to cold (19°C) for 2 h, 17 of 32 younger subjects (aged 23–35 years) and 2 of 24 elderly subjects (aged 38–65 years) showed a substantial FDG uptake into adipose tissue of the supraclavicular and paraspinal regions, whereas they showed no detectable uptake when kept warm (27°C). Histological examinations confirmed the presence of brown adipocytes in these regions. The cold-activated FDG uptake was increased in winter compared with summer (P < 0.001) and was inversely related to BMI (P < 0.001) and total (P < 0.01) and visceral (P < 0.001) fat areas estimated from CT image at the umbilical level.CONCLUSIONSOur findings, being against the conventional view, indicate the high incidence of metabolically active BAT in adult humans and suggest a role in the control of body temperature and adiposity.

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S U M M A R Y Galectin, an animal lectin that recognizes b-galactoside of glycoconjugates, is abundant in the gut. This IHC study showed the subtype-specific localization of galectin in the mouse digestive tract. Mucosal epithelium showed region/cell-specific localization of each galectin subtype. Gastric mucous cells exhibited intense immunoreactions for galectin-2 and galectin-4/6 with a limited localization of galectin-3 at the surface of the gastric mucosa. Electron microscopically, galectin-3 immunoreactivity coated indigenous bacteria on the gastric surface mucous cells. Epithelial cells in the small intestine showed characteristic localizations of galectin-2 and galectin-4/6 in the cytoplasm of goblet cells and the baso-lateral membrane of enterocytes in association with maturation, respectively. Galectin-3 expressed only at the villus tips was concentrated at the myosin-rich terminal web of fully matured enterocytes. Epithelial cells of the large intestine contained intense immunoreactions for galectin-3 and galectin-4/6 but not for galectin-2. The stratified squamous epithelium of the forestomach was immunoreactive for galectin-3 and galectin-7, but the basal layer lacked galectin-3 immunoreactivity. Outside the epithelium, only galectin-1 was localized in the connective tissue, smooth muscles, and neuronal cell bodies. The subtype-specific localization of galectin suggests its important roles in host-pathogen interaction and epithelial homeostasis such as membrane polarization and trafficking in the gut. GALECTIN is a b-galactoside-binding lectin, which to date consists of 15 members (galectin-1 to galectin-15) in mammals and is broadly distributed in a variety of cells and tissues (Leffler et al. 2004). Galectin is likely secreted extracellularly through a non-classical unknown pathway because it lacks a signal sequence essential for insertion into the endoplasmic reticulum (Hughes 1999). Extracellular galectin may mediate cell-cell or cell-matrix adhesion by recognizing cell surface glycoproteins and glycolipids or glycosylated extracellular matrix (Hughes 2001). It also seems capable of regulating cell signaling and membrane trafficking by cross-linking the cell surface receptors (Rabinovich et al. 2007a). A special type of galectin (galectin-3) is involved in host-pathogen interaction through the recognition of a surface carbohydrate of microorganisms (Sato and Nieminen 2004). In contrast, the predominant localization of galectin in the cytoplasm has been frequently observed, suggesting an additional possibility that galectin operates intracellularly to cell proliferation, differentiation, and apoptosis (Hsu and Liu 2004).In the mouse, nine subtypes of galectin (galectin-1, -2, -3, -4, -6, -7, -8, -9, and -12) have been reported to be expressed in a tissue/cell-specific manner. The digestive tract is one of the organs rich in galectin; we previously showed at the mRNA level that at least six subtypes of galectin (galectin-2, -3, -4, -6, -7, and -9) were intensely and continuously expressed from t...

Lactate plays an important role as an alternative energy substrate, especially in conditions with a decreased utility of glucose. Proton-coupled monocarboxylate transporters (MCTs) are essential for the transport of lactate, ketone bodies, and other monocarboxylates through the plasma membrane and may contribute to the net transport of lactate through the placental barrier. The present study examined the expression profile and subcellular localization of MCTs in the mouse placenta. An in situ hybridization survey of all MCT subtypes detected intense mRNA expressions of MCT1, MCT4, and MCT9 as well as GLUT1 in the placenta from gestational day 11.5.The expression of MCT mRNAs decreased in the intensity at the end of gestation in contrast to a consistently intense expression of GLUT1 mRNA.Immunohistochemically, MCT1 and MCT4 showed a polarized localization on the maternal side and fetal side of the two cell-layered syncytiotrophoblast, respectively.The membrane-oriented localization of MCTs was supported by the coexistence of CD 147 which recruits MCT to the plasma membrane. However, the subcellular arrangement of MCT1 and MCT4 along the trophoblastic cell membrane was completely opposite of that in the human placenta. Although we cannot exactly explain the reversed localization of MCTs between human and murine placentas, it may be related to differences between humans and mice in the origin of lactate and its utilization by fetuses.3

Impact of stress on diseases including gastrointestinal failure is well-known, but molecular mechanism is not understood. Here we show underlying molecular mechanism using EAE mice. Under stress conditions, EAE caused severe gastrointestinal failure with high-mortality. Mechanistically, autoreactive-pathogenic CD4+ T cells accumulated at specific vessels of boundary area of third-ventricle, thalamus, and dentate-gyrus to establish brain micro-inflammation via stress-gateway reflex. Importantly, induction of brain micro-inflammation at specific vessels by cytokine injection was sufficient to establish fatal gastrointestinal failure. Resulting micro-inflammation activated new neural pathway including neurons in paraventricular-nucleus, dorsomedial-nucleus-of-hypothalamus, and also vagal neurons to cause fatal gastrointestinal failure. Suppression of the brain micro-inflammation or blockage of these neural pathways inhibited the gastrointestinal failure. These results demonstrate direct link between brain micro-inflammation and fatal gastrointestinal disease via establishment of a new neural pathway under stress. They further suggest that brain micro-inflammation around specific vessels could be switch to activate new neural pathway(s) to regulate organ homeostasis.DOI: http://dx.doi.org/10.7554/eLife.25517.001

Peripheral nerves express GLUT1 in both endoneurial blood vessels and the perineurium and utilize glucose as a major energy substrate, as does the brain. However, under conditions of a reduced utilization of glucose, the brain is dependent upon monocarboxylates such as ketone bodies and lactate, being accompanied by an elevated expression of a monocarboxylate transporter (MCT1) in the blood-brain barrier. The present immunohistochemical study aimed to examine the expression of MCT1 in the peripheral nerves of mice. MCT1 immunoreactivity was found in the perineurial sheath and colocalized with GLUT1, while the endoneurial blood vessels expressed GLUT1 only. An intense expression of MCT1 in the perineurium was confirmed by Western blot and in situ hybridization analyses. Ultrastructurally, the MCT1 and GLUT1 immunoreactivities in the thick perineurium showed an intensity gradient decreasing towards the innermost layer. In neonates, the MCT1 immunoreactivity in the perineurium was intense, while the GLUT1 immunoreactivity was faint or absent. These findings suggest that peripheral nerves depend on monocarboxylates as a major energy source and that MCT1 in the perineurium is responsible for the supply of monocarboxylates to nerve fibers and Schwann cells.

SMCT1 (slc5a8) is a sodium-coupled monocarboxylate transporter expressed in the brush border of enterocytes. It regulates the uptake of short-chain fatty acids (SCFAs) produced by bacterial fermentation in the large intestine. Another subtype, SMCT2 (slc5a12), is expressed abundantly in the small intestine, but its precise expression profile remains unknown. The present study using in situ hybridization method, immunohistochemistry, and quantitative PCR analysis examined the distribution and cellular localization of SMCT2 in the digestive tract of mice and compared the expression pattern with those of other transporters for monocarboxylates. While an abundant expression of SMCT2 was found in the jejunum, this was negligible in the duodenum, terminal ileum, and large intestine. In contrast, SMCT1 had predominant expression sites in the large bowel and terminal ileum. Subcellularly, SMCT2 was localized in the brush border of enterocytes in the intestinal villi-as is the case for SMCT1, suggesting its involvement in the uptake of foodderived monocarboxylates such as lactate and acetate. MCT (slc16) is a basolateral type transporter of the gut epithelium and conveys monocarboxylates in an H + -dependent manner. Since among the main subtypes of MCT family only MCT1 was expressed significantly in the small intestine, it is able to function as a counterpart to SMCT2 in this location.

Bone morphogenetic proteins (BMPs), members of the transforming growth factor β (TGFβ) superfamily, play important roles in folliculogenesis in various species; however, little is known about their role in luteal function. In this study, we investigated the expression, regulation, and effects of BMP2, BMP4, and BMP6 in carefully dated human corpora lutea and cultured human luteinized granulosa cells. The mRNA abundance of BMPs was increased in the regressing corpus luteum in vivo (P<.01-.001). Human chorionic gonadotropin (hCG) down-regulated BMP2, BMP4, and BMP6 transcripts both in vivo (P=.05-.001) and in vitro (P<.001), and decreased the mRNA abundance of BMP receptors (BMPR1A, BMPR1B, BMPR2; P<.05-.01) in vitro. Three BMPs were regulated by differential signaling pathways. H89, a protein kinase A inhibitor, increased the expression of both BMP2 (P<.05) and BMP4 (P<.05) while decreasing BMP6 (P<.01). PMA, a protein kinase C activator, decreased both BMP4 and BMP6 expression (P<.0001) while enhancing the mRNA abundance of BMP2 (P<.01). BMPs significantly down-regulated transcripts for LH/choriogonadotropin receptor (LHCGR; P<.001) and steroidogenic acute regulatory protein (STAR; P<.001), whereas up-regulating those of follicular stimulating hormone receptor (FSHR; P<.01) and aromatase (CYP19A1; P<.05-.01) in vitro, possessing an effect opposite to hCG but similar to Activin A. Like Activin A, BMP4 and BMP6 stimulated the expression of Inhibin/Activin subunits with a marked effect on INHBB expression (P<.05-.01). These data confirm that BMPs are increased during luteal regression and negatively regulated by hCG via differential mechanisms, suggesting that BMPs are one of the mediators of luteolysis in women.