Heme biosynthesis regulates BCAA catabolism and thermogenesis in brown adipose tissue.

With age, people tend to accumulate body fat and reduce energy expenditure 1 . Brown (BAT) and beige adipose tissue dissipate heat and increase energy expenditure via the activity of the uncoupling protein UCP1 and other thermogenic futile cycles 2,3 . The activity of brown and beige depots inversely correlates with BMI and age 4-11 , suggesting that promoting thermogenesis may be an effective approach for combating age-related metabolic disease 12-15 . Heme is an enzyme cofactor and signaling molecule that we recently showed to regulate BAT function 16 . Here, we show that heme biosynthesis is the primary contributor to intracellular heme levels in brown adipocytes. Inhibition of heme biosynthesis leads to mitochondrial dysfunction and reduction in UCP1. Although supplementing heme can restore mitochondrial function in heme-synthesis-deficient cells, the downregulation of UCP1 persists due to the accumulation of the heme precursors, particularly propionyl-CoA, which is a product of branched-chain amino acids (BCAA) catabolism. Cold exposure promotes BCAA uptake in BAT, and defects in BCAA catabolism in this tissue hinder thermogenesis 17 . However, BCAAs' contribution to the TCA cycle in BAT and WAT never exceeds 2% of total TCA flux 18 . Our work offers a way to integrate current literature by describing heme biosynthesis as an important metabolic sink for BCAAs.

Deconstructing Adipose Tissue Heterogeneity One Cell at a Time.

As a central coordinator of physiologic metabolism, adipose tissue has long been appreciated as a highly plastic organ that dynamically responds to environmental cues. Once thought of as a homogenous storage depot, recent advances have enabled deep characterizations of the underlying structure and composition of adipose tissue depots. As the obesity and metabolic disease epidemics continue to accelerate due to modern lifestyles and an aging population, elucidation of the underlying mechanisms that control adipose and systemic homeostasis are of critical importance. Within the past decade, the emergence of deep cell profiling at tissue- and, recently, single-cell level has furthered our understanding of the complex dynamics that contribute to tissue function and their implications in disease development. Although many paradigm-shifting findings may lie ahead, profound advances have been made to forward our understanding of the adipose tissue niche in both health and disease. Now widely accepted as a highly heterogenous organ with major roles in metabolic homeostasis, endocrine signaling, and immune function, the study of adipose tissue dynamics has reached a new frontier. In this review, we will provide a synthesis of the latest advances in adipose tissue biology made possible by the use of single-cell technologies, the impact of epigenetic mechanisms on adipose function, and suggest what next steps will further our understanding of the role that adipose tissue plays in systemic physiology.

Selumetinib normalizes Ras/MAPK signaling in clinically relevant neurofibromatosis type 1 minipig tissues in vivo.

BACKGROUND: The MEK1/2 inhibitor selumetinib was recently approved for neurofibromatosis type 1 (NF1)-associated plexiform neurofibromas, but outcomes could be improved and its pharmacodynamic evaluation in other relevant tissues is limited. The aim of this study was to assess selumetinib tissue pharmacokinetics (PK) and pharmacodynamics (PD) using a minipig model of NF1. METHODS: WT (n = 8) and NF1 (n = 8) minipigs received a single oral dose of 7.3 mg/kg selumetinib. Peripheral blood mononuclear cells (PBMCs), cerebral cortex, optic nerve, sciatic nerve, and skin were collected for PK analysis and PD analysis of extracellular regulated kinase phosphorylation (p-ERK) inhibition and transcript biomarkers (DUSP6 & FOS). RESULTS: Key selumetinib PK parameters aligned with those observed in human patients. Selumetinib concentrations were higher in CNS tissues from NF1 compared to WT animals. Inhibition of ERK phosphorylation was achieved in PBMCs (mean 60% reduction), skin (95%), and sciatic nerve (64%) from all minipigs, whereas inhibition of ERK phosphorylation in cerebral cortex was detected only in NF1 animals (71%). Basal p-ERK levels were significantly higher in NF1 minipig optic nerve compared to WT and were reduced to WT levels (60%) with selumetinib. Modulation of transcript biomarkers was observed in all tissues. CONCLUSIONS: Selumetinib reduces MAPK signaling in tissues clinically relevant to NF1, effectively normalizing p-ERK to WT levels in optic nerve but resulting in abnormally low levels of p-ERK in the skin. These results suggest that selumetinib exerts activity in NF1-associated CNS tumors by normalizing Ras/MAPK signaling and may explain common MEK inhibitor-associated dermatologic toxicities.