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Biology subjects

Brent, A. E.

Publications and source records attributed to Brent, A. E..

5 recordsLinked to original sources

SOX9 is part of a combinatorial marker that reveals early development and embryological origins of the mouse brown adipose tissue depots

Brown adipose tissue (BAT) is a mammalian thermogenic tissue that helps to maintain body temperature and provides important metabolic functions. Most brown adipocytes are located in structures called depots, and the development of depots is incompletely understood. Here, we define the embryonic positions in which the three major mouse BAT depots arise using a combination of morphological landmarks and expression of SOX9, a transcription factor that we find, by immunofluorescence and genetic lineage tracing, marks brown adipocyte progenitors from around the time of their exit from dermomyotome. Lineage tracing is also used to confirm the origin of the largest depot, interscapular BAT, in Pax7-positive dermomyotome of somites, and to show that the scapular BAT has a similar embryological origin, while cervical BAT arises from a somitic source outside of the Pax7 lineage. Finally, using Sox9 as part of a novel combinatorial marker, we profile the transcriptome of early brown adipocyte progenitors and pre-adipocytes and model their trajectory, revealing pathways including the paracrine signaling environment, in which brown adipocytes of the major depots likely arise. Our results apply to understanding the earliest stages of development of this novel mammalian tissue.

developmental biology↗

Atg8-LC3 controls systemic nutrient surplus signaling from flies to humans.

Organisms experience constant nutritional flux, and homeostatic mechanisms evolved to operate at the nexus of extreme nutritional states - scarcity and surplus. Thus, we surmised that decoding bidirectional molecular switches that operate at the interface of scarcity response and surplus signaling will enable the development of strategies to treat disorders that arise from nutrient imbalance states. Adipocytes secrete leptin, an interleukin protein, which signals nutrient surplus to the central brain to regulate feeding and energy expenditure. We report that Atg8-LC3-family proteins, best known for their role in autophagy, are required for leptin secretion in Drosophila and human adipocytes. Atg8-LC3 genetic knockdown and point mutations to the Atg8-LC3 interaction motif (AIM/LIR) of leptin, and its functional ortholog in Drosophila, Upd2, disrupt adipokine secretion and increase adipokine retention in human and fly cells. At an organismal level, Atg8-driven Upd2 retention increases organismal resilience to nutrient extremes by rewiring the transcriptome, organismal feeding behavior, and hunger response. Comparative proteomic analyses reveal that LC3 directs leptin to an exosome secretory pathway. We use genetic knockdown in primary human adipocytes to establish that LC3 is required for leptin secretion in a physiologically relevant mammalian system. Hence, we uncover a previously unknown and evolutionarily conserved role for Atg8-LC3 in promoting adipocyte-brain nutrient surplus signaling. We propose that Atg8-LC3s bidirectional role in nutrient sensing-conveying nutrient surplus and responding to nutrient deprivation-enables organisms to manage nutrient flux effectively.

physiology↗

Fat Body Phospholipid State Dictates Hunger Driven Feeding Behavior

Diet-induced obesity (DIO) leads to dysfunctional feeding behavior. However, the precise molecular nodes underlying diet-induced dysregulation of satiety sensing and feeding motivation are poorly understood. The fruit fly is a simple genetic model system yet displays significant evolutionary conservation to mammalian nutrient sensing and energy balance. Using a longitudinal high sugar regime in Drosophila, we sought to address how lipid alteration in fat cells alters feeding behavior. We find that prolonged exposure to HSD degrades the hunger-driven feeding (HDF) response. Lipidomics analysis reveals that longitudinal exposure to HSD significantly alters whole body phospholipid profiles. By performing a systematic screen for phospholipid enzymes, we identify Pect as a critical regulator of hunger-driven feeding. Pect is a rate-limiting enzyme in the phosphatidylethanolamine (PE) biosynthesis pathway and the fly ortholog of human PCYT2. We show that disrupting Pect only in the fat body causes insulin-resistant phenotypes and a loss of hunger-driven feeding. Excitingly, we find that overexpression of Pect restores HSD-induced loss of hunger-driven feeding response. Strikingly human studies have noted a correlation between PCYT2/Pect levels and clinical obesity. Now, our unbiased studies in Drosophila provide specific genetic evidence for Pect in maintaining nutrient sensing during DIO. Our study provides novel insights into the role of phospholipids in interorgan communication of nutrient status. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/472854v4_ufigA1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@1ecf3eorg.highwire.dtl.DTLVardef@b800f2org.highwire.dtl.DTLVardef@461a7eorg.highwire.dtl.DTLVardef@75651c_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

Atg8 licenses adipokine nuclear exit

Adipokines released from the adipocytes function as a systemic adipometer; they impinge on neural circuits to signal nutrient status. On starvation, adipokines must be retained to signal energy deficit; else, it significantly reduces starvation survival. But how fat cells retain adipokines is unclear. Here, we demonstrate that Atg8, a cell-intrinsic autophagy factor, regulates the starvation-induced acute retention of the Leptin Drosophila ortholog Upd2. We show that on starvation, as a direct consequence of Atg8s lipidation, Upd2 accumulates in the nucleus. We illustrate that Upd2s nuclear retention is critical to fat mobilization and increased starvation resilience. Furthermore, nuclear Upd2 promotes the expression of a secreted innate immune gene signature. This hints at an unanticipated connection between adipokine nuclear retention and increased innate immunity. In conclusion, we propose that, during starvation, Atg8s role is not just limited to autophagy but is critical for withholding adipokines in the nucleus to promote starvation resilience. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=178 HEIGHT=200 SRC="FIGDIR/small/428913v5_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1826425org.highwire.dtl.DTLVardef@17cca52org.highwire.dtl.DTLVardef@1c70ac7org.highwire.dtl.DTLVardef@94a024_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIIn fed state Upd2 requires Atg8 for nuclear exit and cytosolic localization. C_LIO_LIAtg8s lipidation on starvation results in Upd2s nuclear accumulation. C_LIO_LIUpd2 nuclear retention on starvation increases fat mobilization and post-starvation hunger. C_LIO_LIOn starvation Upd2 nuclear retention increases expression of a secreted innate immune signature. C_LI

physiology↗

Adipokines set neural tone by regulating synapse number

Energy sensing neural circuits decide to expend or conserve resources by integrating tonic steady-state energy store information with phasic signals for hunger and food intake. Tonic signals, in the form of adipose tissue-derived adipokines, set the baseline level of energy-sensing neuron activity, providing context for interpretation of phasic messages. However, the mechanism by which tonic adipokine information establishes baseline neuronal function is unclear. Here we show that Upd2, a Drosophila Leptin ortholog, regulates actin-based synapse reorganization by reducing inhibitory synaptic contacts, thereby providing a permissive neural tone for insulin release under conditions of nutrient surplus. Unexpectedly, Insulin acts on the same upstream inhibitory neurons to conversely increase synapse number, hence re-instating negative tone. Our results suggest that two surplus-sensing hormonal systems, Leptin/Upd2 and Insulin, converge on a neuronal circuit with opposing outcomes that establish tonic, energy-store-dependent neuron activity. HighlightsO_LIThe adipokine Upd2 regulates number of inhibitory synaptic contacts on Insulin neurons. C_LIO_LIUpd2 activates an actin-regulating complex of Arouser, Basigin, and Gelsolin in target neurons. C_LIO_LIArouser, Basigin, and Gelsolin reduce the extent of inhibitory contact on Insulin neurons. C_LIO_LIInsulin resets negative tone by increasing the number of synaptic contacts made by its own upstream inhibitory neurons. C_LI

physiology↗