Copper-dependent amino oxidase 3 governs selection of metabolic fuels in adipocytes

Abstract

Copper (Cu) has emerged as an important modifier of body lipid metabolism. However, how Cu contributes to the physiology of fat cells remains largely unknown. We found that adipocytes require Cu to establish a balance between main metabolic fuels. Differentiating adipocytes increase their Cu uptake along with the ATP7A-dependent transport of Cu into the secretory pathway to activate a highly up-regulated amino-oxidase copper-containing 3 (AOC3)/semicarbazide-sensitive amine oxidase (SSAO); in vivo, the activity of SSAO depends on the organism’s Cu status. Activated SSAO oppositely regulates uptake of glucose and long-chain fatty acids and remodels the cellular proteome to coordinate changes in fuel availability and related downstream processes, such as glycolysis, de novo lipogenesis, and sphingomyelin/ceramide synthesis. The loss of SSAO-dependent regulation due to Cu deficiency, limited Cu transport to the secretory pathway, or SSAO inactivation shifts metabolism towards lipid-dependent pathways and results in adipocyte hypertrophy and fat accumulation. The results establish a role for Cu homeostasis in adipocyte metabolism and identify SSAO as a regulator of energy utilization processes in adipocytes.

Association between dietary mineral nutrient intake, body mass index, and waist circumference in U.S. adults using quantile regression analysis NHANES 2007–2014

“…In a mouse model of hereditary copper imbalance, copper have been shown to be an endogenous regulator of lipolysis (Krishnamoorthy et al, 2016). Copper deficiency can significantly increase plasma cholesterol, which can also lead to fat cell hypertrophy and fat accumulation (Yang et al, 2018). Therefore, copper might be used as a dietary supplement.…”

Association between Trace Elements and Body Composition Parameters in Endurance Runners

“…We also found a negative correlation with the subscapular skinfold and fat mass. Recently, Cu has emerged as an important modifier of body lipids; a deficiency of Cu causes the inhibition of semicarbazide-sensitive amine oxidase (SSAO) activity-a regulatory enzyme of energy utilization processes in adipocytes that favors adipocyte hypertrophy and fat deposition [35]. It is thus necessary to check this TE in runners, because excess fat mass is negatively related to sport performance [1] Li plays an important role in several physiological functions-neural communication, metabolism and cell proliferation-but a deficit or excess concentrations induce negative or toxic effects [36].…”

Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer

“…Cu is known to influence tumor growth through the stimulation of several cuproenzymes, including Ceruloplasmin (CP), MEK1/2, and Cytochrome C Oxidase (CCO/COX), which are associated with various biological functions [30][31][32][33] . To stimulate these cuproenzymes, Cu is loaded in the secretory pathway via a process that is dependent on ATP7A [34][35][36][37] . Strikingly, we found that ATP7A knockdown significantly increased CCS levels in KRAS IEC-6 cells ( Fig.…”