NBR1 is a critical step in the repression of thermogenesis of p62-deficient adipocytes through PPARγ

Abstract

Activation of non-shivering thermogenesis is considered a promising approach to lower body weight in obesity. p62 deficiency in adipocytes reduces systemic energy expenditure but its role in sustaining mitochondrial function and thermogenesis remains unresolved. NBR1 shares a remarkable structural similarity with p62 and can interact with p62 through their respective PB1 domains. However, the physiological relevance of NBR1 in metabolism, as compared to that of p62, was not clear. Here we show that whole-body and adipocyte-specific ablation of NBR1 reverts the obesity phenotype induced by p62 deficiency by restoring global energy expenditure and thermogenesis in brown adipose tissue. Impaired adrenergic-induced browning of p62-deficient adipocytes is rescued by NBR1 inactivation, unveiling a negative role of NBR1 in thermogenesis under conditions of p62 loss. We demonstrate that upon p62 inactivation, NBR1 represses the activity of PPARγ, establishing an unexplored p62/NBR1-mediated paradigm in adipocyte thermogenesis that is critical for the control of obesity.

De novo lipogenesis fuels adipocyte autophagosome membrane dynamics

“…In addition to its role in autophagy, p62 serves as a signaling hub that participates in multiple pathways, but most notably, p62 regulates beige and brown adipocyte formation. Knockout of p62 in adipose tissue results in obesity, glucose intolerance, and reduced energy expenditure, effects attributed to reductions in brown and beige adipose tissue thermogenesis (Fischer et al, 2020; Huang et al, 2021; Muller et al, 2013). Mechanistically, p62 directs phospho-ATF2 to promoters of thermogenic genes and also functions as co-activator of PPARγ (Fischer et al, 2020; Huang et al, 2021).…”

“…Knockout of p62 in adipose tissue results in obesity, glucose intolerance, and reduced energy expenditure, effects attributed to reductions in brown and beige adipose tissue thermogenesis (Fischer et al, 2020; Huang et al, 2021; Muller et al, 2013). Mechanistically, p62 directs phospho-ATF2 to promoters of thermogenic genes and also functions as co-activator of PPARγ (Fischer et al, 2020; Huang et al, 2021). It is tempting to speculate that FasnKO-mediated increases in adipose tissue p62 as a result of autophagy dysfunction regulate the beiging and metabolic improvements observed in these mice, but FasnKO in vitro does not upregulate Ucp1 under our experimental conditions.…”

Mitophagy Mediates the Beige to White Transition of Human Primary Subcutaneous Adipocytes Ex Vivo

“…This suggests that p62 plays a significant role in the regulation of thermogenesis in BAT. A recent paper has demonstrated that NBR1 is required for the repression of adaptive thermogenesis via decreasing the activity of PPARγ in BAT of p62-deficient mice; thereby, the inhibitory role of NBR1 in thermogenesis in the presence of p62 inactivation was identified [ 87 ]. Based on these studies, further investigations may reveal the role of p62 and NBR1 in the thermogenesis of human brown and beige adipocytes.…”

Bioinformatics analysis of candidate genes and potential therapeutic drugs targeting adipose tissue in obesity

“…Obesity is characterized by increased mass in the adipose tissue, which is linked to the persistent activation of inflammatory pathways in both adipocytes and macrophages living in or invading the adipose tissues [ 10–12 ]. A previous study has revealed that the adipocyte’s p62 is a critical regulator of energy balance and adiposity in vivo [ 13 ]. Moreover, Trayhurn P. demonstrated that adipose hypoxia might be a causative factor for adipose dysfunction in obesity [ 14 ].…”