Brown Adipose YY1 Deficiency Activates Expression of Secreted Proteins Linked to Energy Expenditure and Prevents Diet-Induced Obesity

Abstract

Mitochondrial oxidative and thermogenic functions in brown and beige adipose tissues modulate rates of energy expenditure. It is unclear, however, how beige or white adipose tissue contributes to brown fat thermogenic function or compensates for partial deficiencies in this tissue and protects against obesity. Here, we show that the transcription factor Yin Yang 1 (YY1) in brown adipose tissue activates the canonical thermogenic and uncoupling gene expression program. In contrast, YY1 represses a series of secreted proteins, including fibroblast growth factor 21 (FGF21), bone morphogenetic protein 8b (BMP8b), growth differentiation factor 15 (GDF15), angiopoietin-like 6 (Angptl6), neuromedin B, and nesfatin, linked to energy expenditure. Despite substantial decreases in mitochondrial thermogenic proteins in brown fat, mice lacking YY1 in this tissue are strongly protected against diet-induced obesity and exhibit increased energy expenditure and oxygen consumption in beige and white fat depots. The increased expression of secreted proteins correlates with elevation of energy expenditure and promotion of beige and white fat activation. These results indicate that YY1 in brown adipose tissue controls antagonistic gene expression programs associated with energy balance and maintenance of body weight.T he incidence of obesity has become a global epidemic, leading to an increase in associated pathologies such as cardiovascular disease, type 2 diabetes, and cancer (1). Obesity is the result of a net imbalance between the energy intake and the energy expenditure (2). An important component of energy expenditure is adaptive thermogenesis caused by the heat dissipated in response to lower temperatures or diet and produced in the mitochondria of brown adipose tissue (BAT) and skeletal muscle. In BAT, this thermogenic process is largely dependent on inducible mitochondrial uncoupling respiration mediated by uncoupling protein 1 (UCP1) (3, 4). In addition to brown adipocytes, the presence of clusters of inducible thermogenic adipocytes within subcutaneous white fat depots, referred to as browning, has been proposed as an additional or compensatory site of energy dissipation and body weight control (5-7). Although these adipocytes, named "beige" (or "brite"), are derived from a different developmental lineage than BAT, they express UCP1 and similar thermogenic components (5, 8, 9). Moreover, under some conditions, white adipocytes activate thermogenic processes that contribute to energy expenditure (6, 10). In humans, the presence of these inducible thermogenic adipocytes opens the possibility to identify targets to therapeutically treat obesity. Toward this goal, it is necessary to identify the molecular and cellular mechanisms governing beige or white adipocyte thermogenesis that, despite recent advances (11-15), are currently not completely understood.At the transcriptional level, activation of the canonical thermogenic program in BAT (often in response to adrenergic agonism) (16), involves inducible coactivation of peroxi...

Brown Adipocytes Secrete GDF15 in Response to Thermogenic Activation

“…In the present study, we found that GDF15 is released by brown and beige adipocytes in concert with the thermogenic activation of these cells. This confirmed previous observations by Verdeguer et al (27). GDF15 expression shares a strong transcriptional regulation in response to noradrenergic, β3-adrenergic-mediated pathways, involving cAMP, with other intracellular thermogenic machinery components (e.g., UCP1) and with previously identified brown adipokines (e.g., FGF21, bone morphogenetic protein 8B).…”

Mediation Analysis Supports a Causal Relationship between Maternal Hyperglycemia and Placental DNA Methylation Variations at the Leptin Gene Locus and Cord Blood Leptin Levels

“…This CpG site has recently been characterized as an LEP interaction region (chr7: 127,854,840-127,881,330). Also based on ENCODE data, cg15758240 is in the vicinity of a number of transcription factor binding sites, including YY1 (−99 bp), CEBPB (−144 bp), USF1 (−164 bp), STAT3 (−184 bp), and GATA2 (−204 bp), which has been previously linked to obesity [36][37][38][39][40], suggesting that cg15758240 is located within a genomic region relevant for both fat accretion and transcriptional regulation activity. Hence, we herein add to the current evidence that the harmful effects of maternal hyperglycemia on offspring adiposity and obesity risk is likely to include epigenetic dysregulation of the leptin gene pathway.…”

New insights into the secretory functions of brown adipose tissue

“…In 2012, BMP8b, a member of the Bmp protein family, was identified as a brown adipokine released by brown adipocytes in response to noradrenergically mediated thermogenic stimulus (Whittle et al 2012). Further studies have confirmed that Bmp8b is among the most intensely upregulated genes in murine brown adipocytes exposed to thermogenic stimuli (Verdeguer et al 2015, Quesada-López et al 2016. In contrast with other members of the Bmp family, the role of BMP8b in brown adipocyte biology is not associated with the early stages of adipogenic differentiation but with the secretory activity of fully differentiated brown adipocytes.…”

“…Recently, GDF15 has been reported to exert anorexigenic effects through its action at the brainstem and to contribute towards controlling the energy balance (Breit et al 2017. GDF15 is intensely secreted by brown fat upon exposure to cold conditions and by brown adipocytes after noradrenergic stimulation (Verdeguer et al 2015, Campderros et al 2019 and exerts mostly autocrine effects on macrophages, tuning down their pro-inflammatory responses (Campderros et al 2019). Whether these signalling capacities of brown adipokines towards immune cells are restricted to the local cross-talk between immune cells and adipocytes at adipose depots or have consequences on the systemic immune status of the organism are challenging possibilities that remain to be ascertained in further researches.…”