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Several distinct strategies produce and conserve heat to maintain the body temperature of mammals, each associated with unique physiologies, with consequences for wellness and disease susceptibility r Highly regulated properties of skin offset the total requirement for heat production r We hypothesize that the adipose component of skin is primarily responsible for modulating heat flux; here we evaluate the relative regulation of adipose depots in mouse and human, to test their recruitment to heat production and conservation r We found that insulating mouse dermal white adipose tissue accumulates in response to environmentally and genetically induced cool stress; this layer is one of two adipose depots closely apposed to mouse skin, where the subcutaneous mammary gland fat pads are actively recruited to heat production r In contrast, the body-wide adipose depot associated with human skin produces heat directly, potentially creating an alternative to the centrally regulated brown adipose tissue Ildiko Kasza, PhD, studied biology at the Semmelweis Medical University, Budapest, Hungary, and prepared her PhD thesis on the role of the cellular cholesterol exporter, ABCA1, in cholesterol homeostasis in humans. She started her postdoctoral career with Dr CM Alexander at the University of Wisconsin, where she focused on the mechanisms underlying the profound tumour resistance of mice with a syndecan-1 mutation. She discovered a novel link between the cancer resistance phenotype and the depletion of a specific fat depot under the skin, the so-called dermal white adipose tissue, leading to systemic cold stress. More specifically, she is interested in mammalian skin as a key metabolic regulator, as well as its influence on human disease susceptibility.This article was first published as a preprint.

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Interferon-γ (IFN-γ) is a crucial cytokine for innate and acquired immunity against infections by intracellular bacteria including mycobacteria. Mutations in the genes involved in the IL-12-IFN-γ pathway cause impaired immunity against lowly virulent mycobacteria and lead to Mendelian Susceptibility to Mycobacterial Disease (MSMD). How the mutations differentially affect leukocyte activation signals and lead to different clinical presentations has not been characterized. We previously analyzed a family with autosomal dominant MSMD and found an 818del4 mutation on the IFN-γ receptor gene IFNGR1 leading to high expression of IFN-γ receptor on leukocytes. While IFN-γ-induced IL-12 and TNF-α secretion from peripheral blood mononuclear cells (PBMCs) were low in the patients. IFN-γ and LPS-induced NADPH oxidase priming and hence reactive oxygen species production was normal. We hence cloned the 818del4 mutant and wildtype IFNGR1 into lentiviral vector and expressed the mutant IFNGR1 on human embryonic kidney 293T cells. We found that stimulation with IFN-γ increased the phosphorylation of Akt and activated p47phox through phosphorylation of Erk1/2 in cells expressing 818del4 mutant IFNGR1. Our results implicated that the truncated IFN-γ receptor may transmit differential signals in leukocytes which alter the toll-like receptor signals by activating the Akt activity and contribute to the severity of immunodeficiency in patients with autosomal dominant MSMD.

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