Abstract
Stimulation of thermogenesis in brown adipose tissue (BAT) could have far-reaching health benefits in combatting obesity and obesity-related complications. Apolipoprotein A-IV (ApoA-IV), produced by the gut and the brain in the presence of dietary lipids, is a well-known short-term satiating protein. While our previous studies have demonstrated reduced diet-induced thermogenesis in ApoA-IV-deficient mice, it is unclear whether this reduction is due to a loss of peripheral or central effects of ApoA-IV. We hypothesized that central administration of ApoA-IV stimulates BAT thermogenesis and that sympathetic and sensory innervation is necessary for this action. To test this hypothesis, mice with unilateral denervation of interscapular BAT received central injections of recombinant ApoA-IV protein or artificial cerebrospinal fluid (CSF). The effects of central ApoA-IV on BAT temperature and thermogenesis in mice with unilateral denervation of the intrascapular BAT were monitored using transponder probe implantation, qPCR, and immunoblots. Relative to CSF, central administration of ApoA-IV significantly increased temperature and UCP expression in BAT. However, all of these effects were significantly attenuated or prevented in mice with unilateral denervation. Together, these results clearly demonstrate that ApoA-IV regulates BAT thermogenesis centrally, and this effect is mediated through sympathetic and sensory nerves.
Highlights
Obesity has become a global epidemic and affects more than 30% of the world’s population [1]
Activation of the AMPK pathway leads to an increase in adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), which are two key enzymes for intracellular TG hydrolysis in brown adipose tissue (BAT)
Leptin, TG, and cholesterol in Apolipoprotein A-IV (ApoA-IV)-treated treated mice were comparable to those in cerebrospinal fluid (CSF)-treated mice (Table 1). These findings sugmice were comparable to those in CSF-treated mice (Table 1). These findings suggest that gest that the elevated BAT thermogenesis induced by centrally administered ApoA-IV is the elevated BAT thermogenesis induced by centrally administered ApoA-IV is indepenindependent of insulin, plasma leptin, insulin,and leptin, lipid levels
Summary
Obesity has become a global epidemic and affects more than 30% of the world’s population [1]. Whether BAT is a realistic pharmaceutical target for treating obesity in humans awaits to be further confirmed [4,5], identifying a potent stimulant of BAT thermogenesis may provide a promising avenue for development of new strategies to combat obesity and obesity-related diseases. Dietary lipids stimulate BAT thermogenesis through activation of gut–brain–BAT neurocircuits in lean animals and humans to counteract the energy surplus [6,7,8]. Dietary lipids increase pro-opiomelanocortin (POMC) expression and activate the melanocortin system in the hypothalamus [9,10], leading to the inhibition of food intake [11] and the induction of norepinephrine (NE) from sympathetic nerves in BAT [12,13,14]. The free fatty acids are taken into the mitochondrial matrix and oxidized to promote diet-induced
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