Elevation of hypothalamic ketone bodies induces a decrease in energy expenditures and an increase risk of metabolic disorder.

OBJECTIVE: Ketone bodies (such as ß-hydroxybutyrate or BHB) have been recently proposed as signals involved in brain regulation of energy homeostasis and obesity development. However, the precise role of ketone bodies sensing by the brain, and its impact on metabolic disorder development remains unclear. Nevertheless, partial deletion of the ubiquitous ketone bodies transporter MCT1 in mice (HE mice) results in diet-induced obesity resistance, while there is no alteration under normal chow diet. These results suggest that ketone bodies produced during the high fat diet would be important signals involved in obesity onset. METHODS: In the present study we used a specific BHB infusion of the hypothalamus and analyzed the energy homeostasis of WT or HE mice fed a normal chow diet. RESULTS: Our results indicate that high BHB levels sensed by the hypothalamus disrupt the brain regulation of energy homeostasis. This brain control dysregulation leads to peripheral alterations of energy expenditure mechanisms. CONCLUSIONS: Altogether, the changes induced by high ketone bodies levels sensed by the brain increase the risk of obesity onset in mice.

Pro-inflammatory immunity supports fibrosis advancement in epidermolysis bullosa: intervention with Ang-(1-7).

Recessive dystrophic epidermolysis bullosa (RDEB), a genetic skin blistering disease, is a paradigmatic condition of tissue fragility-driven multi-organ fibrosis. Here, longitudinal analyses of the tissue proteome through the course of naturally developing disease in RDEB mice revealed that increased pro-inflammatory immunity associates with fibrosis evolution. Mechanistically, this fibrosis is a consequence of altered extracellular matrix organization rather than that of increased abundance of major structural proteins. In a humanized system of disease progression, we targeted inflammatory cell fibroblast communication with Ang-(1-7)-an anti-inflammatory heptapeptide of the renin-angiotensin system, which reduced the fibrosis-evoking aptitude of RDEB cells. In vivo, systemic administration of Ang-(1-7) efficiently attenuated progression of multi-organ fibrosis and increased survival of RDEB mice. Collectively, our study shows that selective down-modulation of pro-inflammatory immunity may mitigate injury-induced fibrosis. Furthermore, together with published data, our data highlight molecular diversity among fibrotic conditions. Both findings have direct implications for the design of therapies addressing skin fragility and fibrosis.

Balance and circumstance: The renin angiotensin system in wound healing and fibrosis.

The tissue renin angiotensin system (tRAS) is a locally-acting master-modulator of tissue homeostasis and regeneration. Through these abilities, it is emerging as an attractive target for therapies aiming to restore tissue homeostasis in conditions associated with disturbed wound healing. The tRAS can be divided into two axes - one being pro-inflammatory and pro-fibrotic and one being anti-inflammatory and anti-fibrotic. However, the division of the axes is fuzzy and imperfect as the axes are codependent and the outcome of tRAS activation is determined by the context. Although the tRAS is a local system it shares its key enzymes, ligands and receptors with the systemic RAS and is consequently also targeted by repurposing of drugs developed against the systemic RAS to manage hypertension. With a focus on the skin we will here discuss the tRAS, its involvement in physiological and pathological wound healing, and the therapeutic aptitude of its targeting to treat chronic wounds and fibrosis.

Therapies for genetic extracellular matrix diseases of the skin.

A specialized, highly developed dermal extracellular matrix (ECM) provides the skin with its unique mechano-resilient properties and is vital for organ function. Accordingly, genetically acquired deficiency of dermal ECM proteins or proteins essential for the post-translational modification and homeostasis of the dermal ECM, results in diseases affecting the skin. Some of these diseases are lethal or lead to severe complications for the affected individuals. At present limited efficient and evidence-based treatment options exist for genetic ECM diseases of the skin. There is thus a high unmet medical need, creating an urgent demand to develop improved care for these diseases. Here, by drawing examples from the wealth of research on epidermolysis bullosa, we present the current status of biological and small molecule therapies for genetic ECM diseases with skin manifestations. We discuss challenges, and using existing data to propose strategies and future directions allowing development of more efficacious therapies and advancement of them into clinical practice.