No / Adiponectin reportedly stimulates proliferation and elongation of human scalp hair follicles (HFs) ex vivo. In the current study, we investigated how adiponectin oligomers produced by perifollicular dermal white adipose tissue (dWAT), a potent source of adiponectin isoforms, influence human HF proliferation and pigmentation. To do so, we treated microdissected, organ-cultured HFs in the presence or absence of dWAT with a recombinant human adiponectin oligomer mix, or inhibited dWAT-derived adiponectin using a neutralizing antibody. Multiplex qPCR (Fluidigm) revealed that adiponectin oligomers downregulated pigmentation genes KITLG, PMEL and TYRP1 and Wnt genes AXIN2, LEF1 and WNT10B. In situ hybridization showed that adiponectin downregulated AXIN2 and LEF1, and up-regulated DKK1 within the dermal papilla (DP), a highly unusual transcriptional profile for a putative hair growth-promoting agent. Adiponectin oligomers also downregulated protein expression of the HGF receptor c-Met within the matrix and DP. However, adiponectin did not alter hair matrix keratinocyte proliferation within 48 h ex vivo, irrespective of the presence/absence of dWAT; HF pigmentation (Masson-Fontana histochemistry, tyrosinase activity) was also unchanged. In contrast, neutralizing adiponectin isoforms within HF + dWAT increased proliferation, melanin content and tyrosinase activity but resulted in fewer melanocytes and melanocytic dendrites, as assessed by gp100 immunostaining. These seemingly contradictory effects suggest that adiponectin exerts complex effects upon human HF biology, likely in parallel with the pro-pigmentation effects of dWAT- and DP-derived HGF. Our data suggest that dWAT-derived ratios of adiponectin isoforms and the cleaved, globular version of adiponectin may in fact determine how adiponectin impacts upon follicular pigmentation and growth. / Biotechnology and Biological Science Research Council (BBSRC) iCASE Studentship (awardees: R.P., J.P., recipient: C.N.), co-funded by Unilever, Colworth, UK; NIHR Manchester Biomedical Research Centre, Inflammatory Hair Diseases Programme (Lead: R.P.), University of Miami start-up funds (R.P.), and Frost Endowed Scholarship to R.P. (Dept. of Dermatology).

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La taille finale des organismes dépend de la vitesse et de la durée de croissance. Ces paramètres sont contrôlés par différentes hormones. La production d'hormone stéroïdienne détermine la fin de la période de croissance en déclenchant la maturité sexuelle, alors que la vitesse de croissance est régulée par la voie de signalisation de l’insuline/IGF (IIS). La vitesse de croissance des organismes est influencée par la nutrition. En effet, des défauts de croissance sont observés chez les individus souffrant de carence protéique chronique. La nutrition contrôle la croissance grâce à la voie de signalisation de l’insuline/IGF. Cependant, le mécanisme par lequel la nutrition contrôle la voie IIS est complexe et reste à élucider. Afin d’explorer cette régulation, le laboratoire utilise Drosophila melanogaster comme modèle d’étude. Chez la drosophile, il existe 8 insulin-like peptides (Dilps). Parmi eux, Dilp2 est la principale insuline promouvant la croissance systémique. Elle est produite par des neurones spécialisés appelés les Insulin Producing Cells (IPC), homologues des cellules béta du pancréas. La sécrétion de Dilp2 dans l’hémolymphe, équivalent du sang chez les vertébrés, est précisément ajustée en fonction de la nutrition. Cette régulation implique une communication inter-organe avec le corps gras, homologue du foie et du tissu adipeux blanc. Selon les conditions nutritionnelles, plusieurs signaux dérivés du corps gras (FDS) sont sécrétés et contrôlent la sécrétion de Dilp2. Ces FDS agissent directement ou indirectement sur les IPCs, via des relais neuronaux. Mon projet de thèse avait pour but de découvrir et d’étudier de nouvelles cibles neuronales contrôlant l’activité sécrétrice des IPCs, et par conséquent la croissance systémique, en fonction de la nutrition. J’ai identifié une paire de neurones inhibiteurs des IPCs, que l’on a nommé IPC-Connecting Neurons (ICN). Actifs en carence en acides aminés, ils inhibent la sécrétion des Dilps. J’ai montré que la signalisation EGFR réprime l’activité de ces neurones en condition nourrie, ce qui augmente la sécrétion des Dilps et par conséquent la taille des individus. Cette activation est due à un nouveau ligand d’EGFR : Growth Blocking Peptide (GBP). J’ai montré que ce ligand de type EGF possède des propriétés particulières puisqu’il agit de façon endocrinienne. En effet, en condition nourrie, GBP est sécrété par le corps gras dans l’hémolymphe, et atteint les ICN afin d’activer la signalisation EGFR. En conclusion, nous proposons que GBP produit par le corps gras en condition nourrie active la voie EGFR dans les neurones ICN, lève l’inhibition exercée sur les IPCs et stimule la sécrétion des Dilps. Cependant, les mécanismes moléculaires par lequel le couple GBP/EGFR inhibe l’activité neuronale des ICNs reste à élucider. Ce travail a permis d’identifier un nouveau mode de régulation de la sécrétion des insulines et de la croissance des organismes en fonction de la disponibilité et de la qualité nutritionnelle. / Body growth is tightly regulated by nutrient availability. Upon nutritional shortage, animals harmoniously reduce their body size by modulating the activity of the insulin/IGF signaling pathway (IIS). To understand how nutrition controls the IIS, we used Drosophila melanogaster as a model. Drosophila has a conserved IIS with 8 insulin-like peptides (Dilps), a unique insulin receptor and a conserved downstream signaling cascade. Among the Dilps, Dilp2 is the main growth-promoting factor. Dilp2 is produced by specialized neurons located in the brain, the Insulin-Producing-Cells (IPCs), functionally related to vertebrate beta cells. Dilp2 secretion is precisely adjusted in response to nutrition: it is released in the hemolymph under normal nutrient condition, but not upon dietary amino acid scarcity. This regulation requires several inter-organ cross-talks between the producing neurons and the fat body, which is the equivalent of the vertebrate white adipose tissue and liver. Depending on diet composition, several fat-derived signals (FDS) are secreted into the hemolymph and control Dilp2 secretion from the IPCs. These FDS act either directly or indirectly through a neuronal relay, to control the IPCs secretory activity. The aim of my PhD project was to better understand these regulations and to discover new neuronal relay controlling the IPCs secretory activity and body growth, according to nutrition. I identified a pair of neurons harboring synaptic connections with the IPCs (IPC-connecting neurons, ICNs). I determined that the ICNs activity is maximal upon amino acids shortage and is required to exert a blockage of the neighbouring IPCs. Moreover, in rich nutrient conditions, EGFR signaling prevents activation of the ICNs, allowing Dilp2 release from the IPCs. GBP1 and 2 are EGF-like peptides produced by the fat body in response to amino acids, and they can modify insulin release. However, the neural circuitries at play are unknown. I demonstrated that GBPs are atypical ligands for the EGF receptor (EGFR), with endocrine function. Using ex-vivo brain culture, I showed that the presence of the fat body-derived GBP1 in the hemolymph activates EGFR signaling in the ICNs and alleviates their inhibitory input on the IPCs, allowing Dilp2 release and therefore body growth. In conclusion, I identified a novel neural circuitry responding to fat-derived EGF-like GBPs, coupling dietary amino acids to the release of insulin-like peptides and systemic growth.

Genom styrning av finansiella medel har gröna obligationer fått en viktig roll i utvecklingen mot ett miljömässigt hållbart samhälle. Extern granskning av gröna obligationer styrs idag genom frivilliga marknadsstandarder, varav GBP är den vanligaste. Dessutom har EU nyligen presenterat en egen frivillig standard med särskild tillsyn. Bättre tillgång till klimatrelaterad information samt tydliga och gemensamma definitioner av gröna aktiviteter är förutsättningar för att investerare mer effektivt ska flytta kapital till miljömässigt hållbara verksamheter för att stötta omställningen till en mindre fossilbaserad ekonomi. I den här uppsatsen visas att dagens betygsättning, olika bedömningsmetoder till trots, torde vara relativt pålitlig, men att det finns utrymme att önska högre jämförbarhet och därmed ökad investerartillit. Tydligare marknadsstandarder kan vara en viktig aspekt för att öka betygens pålitlighet allt eftersom marknaden för gröna obligationer expanderar. Analysen visar att lagstiftning som leder till ökad mängd publicerad granskning genom gröna betyg torde gynna transparensen samtidigt som ryktesrisken vid intressekonflikter bör innebära motvillighet gentemot felaktig bedömning. Samtidigt kan överdriven reglering begränsa möjligheterna för innovation, utveckling och expansion av marknaden som helhet. Det torde därmed vara i lagstiftarens intresse att inte införa alltför sträng reglering, eftersom risk att inte kunna uppnå den finansiering av klimatmålen som önskas då uppstår. Eftersom gröna obligationer är ett internationellt fenomen behöver världens länder arbeta tillsammans mot gemensamma standarder i syfte att nå klimatmålen.  I det fall tvingande reglering ska införas bör den vara på som lägst EU-nivå. För marknadsbalans mellan aktörerna och jämförbarhet mellan obligationerna är det viktigt att regleringen inte upplevs otydlig. Regleringen måste dessutom vara generell och så pass flexibel att den kan möta teknologisk utveckling och förändrade förhållanden på marknaderna utan att processen blir för långdragen. Så länge målet är att ha en europeisk kapitalmarknad där aktörerna kan tillhandahålla finansiella tjänster nationsövergripande krävs finansiell tillsyn som inte stannar vid nationsgränserna. På sikt torde Esma vara lämpligast att överse samtliga granskare av gröna obligationer verksamma på den europeiska marknaden. För detta krävs utökad reglering som ger Esma ökad behörighet såväl som ökade resurser för att effektivt kunna utföra tillsynsarbetet. / Through the management of financial resources, green bonds have received an important role in the development towards an environmentally sustainable society. External review of green bonds is today subject to voluntary market standards, of which GBP is the most common. In addition, the EU has recently presented its own voluntary standard, which includes supervision. Better access to climate-related information and clear and harmonised definitions of green activities are prerequisites for investors to move capital more efficiently to environmentally sustainable businesses to support the transition to a less fossil-based economy. With this paper it is shown that the current rating, despite different assessment methods, should be relatively reliable, but that there is room to wish for higher comparability and thus increased investor confidence. Clearer market standards can be an important aspect in increasing the reliability of ratings as the market for green bonds expands. The analysis shows that legislation that leads to an increased number of published reviews through green ratings should promote transparency, while the risk of rumors in the event of conflicts of interest should imply reluctance to make incorrect assessments. At the same time, excessive regulation may limit the opportunities for innovation, development and expansion of the market as a whole. Thus, it should be in the interest of the legislator not to introduce a regulation which is too strict, as the risk of not being able to achieve the desired financing of the climate goals then arises. As green bonds are an international phenomenon, all countries need to work together towards common standards in order to achieve the purpose of the climate goals. In the event that mandatory regulation is to be introduced, it should at least be at EU level. For market balance between the market participants as well as comparability between the bonds, it is important that the regulation is not perceived as unclear. In addition, regulation must be general and flexible enough to meet technological developments and new market conditions without the process becoming too lengthy. As long as the goal is to have a European capital market where market participants can provide financial services nationwide, financial supervision that does not stop at national borders is required. In the long run, ESMA should be the most appropriate authority to oversee all examiners of green bonds operating in the European market. This requires increased regulation that gives ESMA increased authority, as well as increased resources in order to be able to carry out the supervisory work effectively.