Systemic β-adrenergic stimulation of thermogenesis is not accompanied by brown adipose tissue activity in humans

Abstract

Brown adipose tissue (BAT) is currently considered as a target to combat obesity and diabetes in humans. BAT is densely innervated by the sympathetic nervous system (SNS) and can be stimulated by β-adrenergic agonists, at least in animals. However, the exact role of the β-adrenergic part of the SNS in BAT activation in humans is not known yet. In this study, we measured BAT activity by 2-deoxy-2-[(18)F]fluoro-d-glucose ([(18)F]FDG) positron emission tomography/computed tomography imaging in 10 lean men during systemic infusion of the nonselective β-agonist isoprenaline (ISO) and compared this with cold-activated BAT activity. ISO successfully mimicked sympathetic stimulation as shown by increased cardiovascular and metabolic activity. Energy expenditure increased to similar levels as during cold exposure. Surprisingly, BAT was not activated during β-adrenergic stimulation. We next examined whether the high plasma free fatty acid (FFA) levels induced by ISO competed with glucose ([(18)F]FDG) uptake in BAT locations by blocking lipolysis with acipimox (ACI). ACI successfully lowered plasma FFA, but did not increase [(18)F]FDG-uptake in BAT. We therefore conclude that systemic nonselective β-adrenergic stimulation by ISO at concentrations that increase energy expenditure to the same extent as cold exposure does not activate BAT in humans, indicating that other tissues are responsible for the increased β-adrenergic thermogenesis.

FIG. 1.

ISO- and cold-induced thermogenesis. A: Energy expenditure during baseline and the three ISO doses. B: Energy expenditure during baseline and cold exposure. C: Relationship between the plasma NE level and cold-induced thermogenesis. Values are expressed as means ± SD. *P < 0.05, **P < 0.001, ISO (n = 10) and cold exposure (n = 10).

FIG. 2.

BAT activity during ISO infusion and cold exposure. A: CT image of the supraclavicular area. B: Cold exposure [¹⁸F]FDG PET/CT image showing cold-activated BAT. C: ISO [¹⁸F]FDG PET/CT image showing no BAT activity during ISO. D: ISO + ACI [¹⁸F]FDG PET/CT image showing no effect on [¹⁸F]FDG uptake in supraclavicular BAT. E: Cold exposure [¹⁸F]FDG PET/CT image of the upper body showing BAT activity in the neck, supraclavicular, paraspinal, para-aortic, axillary, mediastinal, and perirenal regions. F: ISO [¹⁸F]FDG PET/CT image showing no BAT activity during ISO. G: ISO + ACI [¹⁸F]FDG PET/CT image showing no effect on [¹⁸F]FDG uptake in BAT locations. H: SUV mean values for BAT, SM, and WAT during cold exposure, ISO, and ISO + ACI; ISO (n = 10), ISO + ACI (n = 5). (A high-quality digital representation of this figure is available in the online issue.)

FIG. 3.

The effects of ACI on FFA levels, substrate use, energy expenditure, and [¹⁸F]FDG uptake. A: Plasma FFA levels during ISO and ISO + ACI. B: Respiratory exchange ratio during ISO and ISO + ACI. C: Energy expenditure during ISO and ISO + ACI. D: The left panel shows the three-dimensional reconstructed PET images in five subjects during ISO infusion indicating no brown fat activity and a low [¹⁸F]FDG uptake in the heart. The right panel shows the same individuals during ISO in combination with ACI. ACI increases [¹⁸F]FDG uptake in the heart as indicated by the black arrows; however, not in BAT locations. Values are expressed as means ± SD. *Significant difference between ISO and ISO + ACI (P < 0.05), **P < 0.001, †significant difference (P < 0.05) between ISO + ACI dose and baseline, ISO (n = 10) ISO + ACI (n = 5).