Based on the seminal observation by Cannon and Nedergaard 1 that human PET scans sometimes depicted a symmetric cold induced uptake of FDG-glucose, three independent studies, published in April 2009, demonstrated metabolically highly active brown adipose tissue (BAT) in adult humans [2][3][4] . Subsequent investigations demonstrated an inverse association of obesity and type 2 diabetes mellitus and the presence of active BAT [5][6][7] . A unique characteristic of BAT is the expression of uncoupling protein 1 (UCP1, also known as thermogenin). Activation of this transmembrane protein by fatty acids in response to adrenergic signaling short-circuits the inner mitochondrial membrane's proton gradient thereby uncoupling oxidative phosphorylation from ATP synthesis. Hence, chemical energy stored in the gradient is dissipated as heat allowing for efficient direct thermogenesis without shivering 8 . This adaptive defense against cold has been examined extensively in rodents and many aspects of BAT development and function have been elucidated. In rodents it is evident 3 that not only the distinct thermogenic BAT organ located in the interscapular region (iBAT) consists of brown adipocytes, but that a second type of brown adipocytes, so-called beige or brite cells can appear in white adipose tissue (WAT) depots in response to cold or 3-adrenergic stimuli 9,10 . Recently, lineage tracing experiments revealed that the two cell types have a different developmental origin 11 . While classical brown adipocytes and skeletal muscle cells arise from precursors in the dermomyotome 12 , beige/brite cells seem to originate from endothelial and perivascular cells within WAT depots [13][14][15] . A recent study by Wu et al suggests that the previously described depots of human BAT are of the beige/brite type and raises the question whether humans altogether lack classical brown adipocytes 16 , this has also been the topic of a recent review 17 . Histomorphological studies performed in the 1970s indicated the existence of brown adipocytes within the interscapular region in human infants and that these disappeared with age 18 . Using a combination of high resolution imaging techniques and morphological and biochemical analyses, we tested the hypothesis that human infants, like small mammals, possess an anatomically distinguishable iBAT depot consisting of classical brown adipocytes, a cell type so far not proven to exist in humans.In an attempt to visualize potential iBAT in humans we performed post mortem MR imaging of eight human infants. Using the fat fraction method 19 we did not only identify BAT depots in the supraclavicular region, but importantly also a fat depot in the interscapular region presenting with an intermediate fat fraction as opposed to the high fat fraction of the surrounding subcutaneous WAT (Supplementary Fig. 1). Using a three dimensional reconstruction we were able to compute the volume of the tissue depot with an average (±SD) volume of 3.6±2.4 ml. Figure 1 displays a representative reconstruction of the iBAT...

Fever has been shown to be elicited by prostaglandin E(2) (PGE(2)) binding to its receptors on thermoregulatory neurons in the anterior hypothalamus. The signals that trigger PGE(2) production are thought to include proinflammatory cytokines, such as IL-6. However, although the presence of IL-6 is critical for fever, IL-6 by itself is not or only weakly pyrogenic. Here we examined the relationship between IL-6 and PGE(2) in lipopolysaccharide (LPS)-induced fever. Immune-challenged IL-6 knockout mice did not produce fever, in contrast to wild-type mice, but the expression of the inducible PGE(2)-synthesizing enzymes, cyclooxygenase-2 and microsomal prostaglandin E synthase-1, was similarly up-regulated in the hypothalamus of both genotypes, which also displayed similarly elevated PGE(2) levels in the cerebrospinal fluid. Nevertheless, both wild-type and knockout mice displayed a febrile response to graded concentrations of PGE(2) injected into the lateral ventricle. There was no major genotype difference in the expression of IL-1beta and TNFalpha or their receptors, and pretreatment of IL-6 knockout mice with soluble TNFalpha receptor ip or intracerebroventricularly or a cyclooxygenase-2 inhibitor ip did not abolish the LPS unresponsiveness. Hence, although IL-6 knockout mice have both an intact PGE(2) synthesis and an intact fever-generating pathway downstream of PGE(2), endogenously produced PGE(2) is not sufficient to produce fever in the absence of IL-6. The findings suggest that IL-6 controls some factor(s) in the inflammatory cascade, which render(s) IL-6 knockout mice refractory to the pyrogenic action of PGE(2), or that it is involved in the mechanisms that govern release of synthesized PGE(2) onto its target neurons.

Inflammation-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis has been suggested to depend on prostaglandins, but the prostaglandin species and the prostaglandin-synthesizing enzymes that are responsible have not been fully identified. Here, we examined HPA axis activation in mice after genetic deletion or pharmacological inhibition of prostaglandin E 2 -synthesizing enzymes, including cyclooxygenase-1 (Cox-1), Cox-2, and microsomal prostaglandin E synthase-1 (mPGES-1). After immune challenge by intraperitoneal injection of lipopolysaccharide, the rapid stress hormone responses were intact after Cox-2 inhibition and unaffected by mPGES-1 deletion, whereas unselective Cox inhibition blunted these responses, implying the involvement of Cox-1. However, mPGES-1-deficient mice showed attenuated transcriptional activation of corticotropin-releasing hormone (CRH) that was followed by attenuated plasma concentrations of adrenocorticotropic hormone and corticosterone. Cox-2 inhibition similarly blunted the delayed corticosterone response and further attenuated corticosterone release in mPGES-1 knock-out mice. The expression of the c-fos gene, an index of synaptic activation, was maintained in the paraventricular hypothalamic nucleus and its brainstem afferents both after unselective and Cox-2 selective inhibition as well as in Cox-1, Cox-2, and mPGES-1 knock-out mice. These findings point to a mechanism by which (1) neuronal afferent signaling via brainstem autonomic relay nuclei and downstream Cox-1-dependent prostaglandin release and (2) humoral, CRH transcription-dependent signaling through induced Cox-2 and mPGES-1 elicited PGE 2 synthesis, shown to occur in brain vascular cells, play distinct, but temporally supplementary roles for the stress hormone response to inflammation.

Recent work demonstrated that the febrile response to peripheral immune stimulation with proinflammatory cytokine IL-1beta or bacterial wall lipopolysaccharide (LPS) is mediated by induced synthesis of prostaglandin E(2) by the terminal enzyme microsomal prostaglandin E synthase-1 (mPGES-1). The present study examined whether a similar mechanism might also mediate the anorexia induced by these inflammatory agents. Transgenic mice with a deletion of the Ptges gene, which encodes mPGES-1, and wild-type controls were injected intraperitoneally with IL-1beta, LPS, or saline. Mice were free fed, and food intake was continuously monitored with an automated system for 12 h. Body weight was recorded every 24 h for 4 days. The IL-1beta induced anorexia in wild-type but not knock-out mice, and so it was almost completely dependent on mPGES-1. In contrast, LPS induced anorexia of the same magnitude in both phenotypes, and hence it was independent of mPGES-1. However, when the mice were prestarved for 22 h, LPS induced anorexia and concomitant body weight loss in the knock-out animals that was attenuated compared with the wild-type controls. These data suggest that IL-1beta and LPS induce anorexia by distinct immune-to-brain signaling pathways and that the anorexia induced by LPS is mediated by a mechanism different from the fever induced by LPS. However, nutritional state and/or motivational factors also seem to influence the pathways for immune signaling to the brain. Furthermore, both IL-1beta and LPS caused reduced meal size but not meal frequency, suggesting that both agents exerted an anhedonic effect during these experimental conditions.