Human Multipotent Adipose-Derived Stem Cells Differentiate into Functional Brown Adipocytes

Abstract

In contrast to the earlier contention, adult humans have been shown recently to possess active brown adipose tissue with a potential of being of metabolic significance. Up to now, brown fat precursor cells have not been available for human studies. We have shown previously that human multipotent adipose-derived stem (hMADS) cells exhibit a normal karyotype and high self-renewal ability; they are known to differentiate into cells that exhibit the key properties of human white adipocytes, that is, uncoupling protein two expression, insulin-stimulated glucose uptake, lipolysis in response to b-agonists and atrial natriuretic peptide, and release of adiponectin and leptin. Herein, we show that, upon chronic exposure to a specific PPARc but not to a PPARb/d or a PPARa agonist, hMADS cell-derived white adipocytes are able to switch to a brown phenotype by expressing both uncoupling protein one (UCP1) and CIDEA mRNA. This switch is accompanied by an increase in oxygen consumption and uncoupling. The expression of UCP1 protein is associated to stimulation of respiration by b-AR agonists, including b3-AR agonist. Thus, hMADS cells represent an invaluable cell model to screen for drugs stimulating the formation and/or the uncoupling capacity of human brown adipocytes that could help to dissipate excess caloric intake of individuals.

Biological aging alters circadian mechanisms in murine adipose tissue depots

“…While cell signaling related pathways account for >25% of the top 50 pathways detected in all tissues, those related to the adrenergic receptor are detected readily in BAT and WAT but not liver (Table 3). This is consistent with the large body of evidence supporting a role for adrenergic signaling in regulating lipolysis and/or differentiation in adipose depots (Lafontan et al 1985;Houstek et al 1990;Rehnmark et al 1990;Elabd et al 2009). Total body NMR was conducted on n05 or 6 animals per age cohort at the completion of the activity/behavioral aspects of the study immediately prior to euthanasia.…”

Pioglitazone reduces cold-induced brown fat glucose uptake despite induction of browning in cultured human adipocytes: a randomised, controlled trial in humans

“…TZDs also induce browning in human adipocyte culture models [13] and rosiglitazone is used almost universally to promote differentiation and browning of human cultured brown adipocytes [13][14][15][16][17]. Rosiglitazone and, to a lesser extent, pioglitazone were widely prescribed for type 2 diabetes until safety concerns were raised (primarily with rosiglitazone [18]), leaving pioglitazone as the predominantly prescribed TZD worldwide [19].…”

Brown and beige fat: development, function and therapeutic potential

“…However, it is known that human WAT contains precursor cells that are capable of expressing UCP1 and other brown and/or beige characteristics, particularly in response to PPAR-γ activation 36 . Additionally, it was (and still is) unclear whether the deposits of UCP1-expressing adipocytes identified by fluorodeoxyglucose positron emission tomography (FDG-PET) in adult humans are analogous to beige or brown fat.…”

“…TZDs induce UCP1 expression and increase mitochondrial biogenesis in adipocytes from mice and humans 12,36,123 . This enables TZDtreated adipocytes to undergo UCP1-mediated increases in respiration in response to β-adrenergic activators 12,36,43 . Mechanistically, TZDs seem to act in large part through Prdm16 to activate a thermogenic program.…”