Adverse Food Reactions: Physiological and Ecological Perspectives.

While food is essential for survival, it can also cause a variety of harmful effects, ranging from intolerance to specific nutrients to celiac disease and food allergies. In addition to nutrients, foods contain myriads of substances that can have either beneficial or detrimental effects on the animals consuming them. Consequently, all animals evolved defense mechanisms that protect them from harmful food components. These "antitoxin" defenses have some parallels with antimicrobial defenses and operate at a cost to the animal's fitness. These costs outweigh benefits when defense responses are exaggerated or mistargeted, resulting in adverse reactions to foods. Additionally, pathological effects of foods can stem from insufficient defenses, due to unabated toxicity of harmful food components. We discuss the structure of antitoxin defenses and how their failures can lead to a variety of adverse food reactions.

Distinct signaling and transcriptional pathways regulate peri-weaning development and cold-induced recruitment of beige adipocytes.

Adipose tissue provides a defense against starvation and environmental cold. These dichotomous functions are performed by three distinct cell types: energy-storing white adipocytes, and thermogenic beige and brown adipocytes. Previous studies have demonstrated that exposure to environmental cold stimulates the recruitment of beige adipocytes in the white adipose tissue (WAT) of mice and humans, a process that has been extensively investigated. However, beige adipose tissue also develops during the peri-weaning period in mice, a developmental program that remains poorly understood. Here, we address this gap in our knowledge using genetic, imaging, physiologic, and genomic approaches. We find that, unlike cold-induced recruitment in adult animals, peri-weaning development of beige adipocytes occurs in a temperature- and sympathetic nerve-independent manner. Instead, the transcription factor B cell leukemia/lymphoma 6 (BCL6) acts in a cell-autonomous manner to regulate the commitment but not the maintenance phase of beige adipogenesis. Genome-wide RNA-sequencing (seq) studies reveal that BCL6 regulates a core set of genes involved in fatty acid oxidation and mitochondrial uncoupling, which are necessary for development of functional beige adipocytes. Together, our findings demonstrate that distinct transcriptional and signaling mechanisms control peri-weaning development and cold-induced recruitment of beige adipocytes in mammals.

BCL6 regulates brown adipocyte dormancy to maintain thermogenic reserve and fitness.

Brown adipocytes provide a metabolic defense against environmental cold but become dormant as mammals habituate to warm environments. Although dormancy is a regulated response in brown adipocytes to environmental warmth, its transcriptional mechanisms and functional importance are unknown. Here, we identify B cell leukemia/lymphoma 6 (BCL6) as a critical regulator of dormancy in brown adipocytes but not for their commitment, differentiation, or cold-induced activation. In a temperature-dependent manner, BCL6 suppresses apoptosis, fatty acid storage, and coupled respiration to maintain thermogenic fitness during dormancy. Mechanistically, BCL6 remodels the epigenome of brown adipocytes to enforce brown and oppose white adipocyte cellular identity. Thus, unlike other thermogenic regulators, BCL6 is specifically required for maintaining thermogenic fitness when mammals acclimate to environmental warmth.

Aster: A New Star in Cholesterol Trafficking.

Life evolved in an aqueous environment, necessitating the evolution of carrier proteins to shuttle lipophilic molecules within and between cells. Sandhu et. al. (2018) report the discovery of a long-sought-after cholesterol carrier protein, named Aster, which transports cholesterol from the plasma membrane to the endoplasmic reticulum.

Tissue Immunometabolism: Development, Physiology, and Pathobiology.

Evolution of metazoans resulted in the specialization of cellular and tissue function. This was accomplished by division of labor, which allowed tissue parenchymal cells to prioritize their core functions while ancillary functions were delegated to tissue accessory cells, such as immune, stromal, and endothelial cells. In metabolic organs, the accessory cells communicate with their clients, the tissue parenchymal cells, to optimize cellular processes, allowing organisms to adapt to changes in their environment. Here, we discuss tissue immunometabolism from this vantage point and use examples from adipose tissues (white, beige, and brown) and liver to outline the general principles by which accessory cells support metabolic homeostasis in parenchymal cells. A corollary of this model is that disruption of communication between client and accessory cells might predispose metabolic organs to the development of disease.

Insulin Signaling in a Bit of a Jam.

In this issue of Cell, Okin and Medzhitov report that sustained inflammation promotes hyperglycemia by targeting the mevalonate pathway. This represents an important step forward in understanding the mechanisms underlying the association between chronic low-grade inflammation and disruption of normal tissue functions in metabolic diseases.

ERG Activates the YAP1 Transcriptional Program and Induces the Development of Age-Related Prostate Tumors.

The significance of ERG in human prostate cancer is unclear because mouse prostate is resistant to ERG-mediated transformation. We determined that ERG activates the transcriptional program regulated by YAP1 of the Hippo signaling pathway and found that prostate-specific activation of either ERG or YAP1 in mice induces similar transcriptional changes and results in age-related prostate tumors. ERG binds to chromatin regions occupied by TEAD/YAP1 and transactivates Hippo target genes. In addition, in human luminal-type prostate cancer cells, ERG binds to the promoter of YAP1 and is necessary for YAP1 expression. These results provide direct genetic evidence of a causal role for ERG in prostate cancer and reveal a connection between ERG and the Hippo signaling pathway.

GSK3-mediated instability of tubulin polymers is responsible for the failure of immature CD4+CD8+ thymocytes to polarize their MTOC in response to TCR stimulation.

Although mature T cells divide and differentiate when they receive strong TCR stimulation, most immature CD4+CD8+ thymocytes die. The molecular basis for this marked difference in response is not known. Observations that TCR-stimulated CD4+CD8+ thymocytes fail to polarize their microtubule-organizing center (MTOC), one of the first events that occurs upon antigen activation of mature T cells, suggests that TCR signaling routes in immature and mature T cells diverge early and upstream of MTOC polarization. To better understand the source of the divergence, we examined the molecular basis for the difference in TCR-mediated MTOC polarization. We show that unstable microtubules are a feature of immature murine CD4+CD8+ thymocytes, which also exhibit higher levels of glycogen synthase kinase 3 (GSK3) activity, a known inhibitor of microtubule stability. Importantly, CD4+CD8+ thymocytes gained the ability to polarize their MTOC in response to TCR signals when GSK3 activity was inhibited. GSK3 inhibition also abrogated TCR-mediated apoptosis of immature thymocytes. Together, our results suggest that a developmentally regulated difference in GSK3 activity has a major influence on immature CD4+CD8+ thymocyte versus mature T-cell responses to TCR stimulation.