Brown adipose tissue lipoprotein and glucose disposal is not determined by thermogenesis in uncoupling protein 1-deficient mice

Abstract

Adaptive thermogenesis is highly dependent on uncoupling protein 1 (UCP1), a protein expressed by thermogenic adipocytes present in brown and white adipose tissues (BAT, WAT). Thermogenic capacity of human and mouse BAT can be measured by positron emission tomography-computed tomography (PET-CT) quantifying the uptake of 18F-fluodeoxyglucose or lipid tracers. BAT activation is typically studied in response to cold exposure or treatment with beta-3-adrenergic receptor agonists such as CL316,243. Currently, it is unknown whether cold-stimulated uptake of glucose or lipid tracers is a good surrogate marker of UCP1-mediated thermogenesis. In metabolic studies using radiolabelled tracers we found that glucose uptake is increased in mildly activated BAT of Ucp1-/- versus WT mice kept at subthermoneutral temperature. Conversely, lower glucose disposal was detected after full thermogenic activation achieved by sustained cold exposure or CL316,243 treatment. In contrast, uptake of lipoprotein-derived fatty acids into chronically activated thermogenic adipose tissues was substantially increased in UCP1-deficient mice. This effect is linked to higher sympathetic tone in adipose tissues of Ucp1-/- mice, as indicated by elevated levels of thermogenic genes in BAT and WAT. Thus, glucose and lipoprotein handling does not necessarily reflect UCP1-dependent thermogenic activity, but especially lipid uptake rather mirrors sympathetic activation of adipose tissues.

Dose-Dependent Effect of Melatonin on BAT Thermogenesis in Zücker Diabetic Fatty Rat: Future Clinical Implications for Obesity

“…Fatty acid β-oxidation fuels the increase in uncoupled mitochondrial respiration and contributes to inducing the expression of thermogenic genes such as UCP1 [ 71 ]. UCP1 is a hallmark of brown adipocytes and plays a pivotal role in BAT thermogenic function since it confers to brown adipocytes their specific ability to dissipate the proton gradient as heat, and its downregulation or absence has been reported to be associated with impaired BAT thermogenic capacity and lower EE [ 72 , 73 , 74 ]. The efficacy of melatonin to induce UCP1 expression in iBAT has already been demonstrated by other groups in experimental ageing and melatonin deficient models, and the melatonin doses offered to animals have ranged from 1 to 10 mg/kg.bw [ 64 , 65 , 66 , 75 ].…”

Susceptibility to diet induced obesity at thermoneutral conditions is independent of UCP1

“…Since UCP1 in BAT is inactive at thermoneutrality, the lack of thermogenic BAT function should be without consequences for energy balance. Indeed, several studies using the established UCP1-KO mouse model originally generated by Leslie Kozak and coworkers confirmed this expectation (Enerbäck et al 1997; Liu et al 2003; Zietak and Kozak 2016; Winn et al 2017; Maurer et al 2020; Fischer et al 2020). In contrast, other studies reported that UCP1 knockout mice are more susceptible to diet induced obesity at thermoneutrality (Feldmann et al 2009; von Essen et al 2017; Rowland et al 2016; Luijten et al 2019; Pahlavani et al 2019).…”

Challenges and limitations in the studies of glycoproteins: A computational chemist's perspective

“…ProDy & DynOmics can be used for glycoprotein modeling. 88 A general purpose of these computational tools is to detect glycosylation terminal regions in deglacosylated proteins and to obtain more correct information about N-and O-linked glycoproteins.…”

“…For instance, GlycoSeq, GlypID, and GlycoPep Evaluator (GPE) were developed for identifying glycopeptide structures in antibodies. ProDy & DynOmics can be used for glycoprotein modeling 88 . A general purpose of these computational tools is to detect glycosylation terminal regions in deglacosylated proteins and to obtain more correct information about N ‐ and O ‐linked glycoproteins.…”