Mammary alveolar epithelial cells convert to brown adipocytes in post-lactating mice

open8siDuring pregnancy and lactation, subcutaneous white adipocytes in the mouse mammary gland transdifferentiate reversibly to milk-secreting epithelial cells. In this study, we demonstrate by transmission electron microscopy that in the post-lactating mammary gland interscapular multilocular adipocytes found close to the mammary alveoli contain milk protein granules. Use of the Cre-loxP recombination system allowed showing that the involuting mammary gland of whey acidic protein-Cre/R26R mice, whose secretory alveolar cells express the lacZ gene during pregnancy, contains some X-Gal-stained and uncoupling protein 1-positive interscapular multilocular adipocytes. These data suggest that during mammary gland involution some milk-secreting epithelial cells in the anterior subcutaneous depot may transdifferentiate to brown adipocytes, highlighting a hitherto unappreciated feature of mouse adipose organ plasticity.openGiordano, Antonio; Perugini, Jessica; Kristensen, David M.; Sartini, Loris; Frontini, Andrea; Kajimura, Shingo; Kristiansen, Karsten; Cinti, SaverioGiordano, Antonio; Perugini, Jessica; Kristensen, David M.; Sartini, Loris; Frontini, Andrea; Kajimura, Shingo; Kristiansen, Karsten; Cinti, Saveri

The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation.

none9sìThe origin of brown adipocytes arising in white adipose tissue (WAT) after cold acclimatization is unclear. Here, we demonstrate that several UCP1-immunoreactive brown adipocytes occurring in WAT after cold acclimatization have a mixed morphology (paucilocular adipocytes). These cells also had a mixed mitochondrioma with classic “brown” and “white” mitochondria, suggesting intermediate steps in the process of direct transformation of white into brown adipocytes (transdifferentiation). Quantitative electron microscopy disclosed that cold exposure (6°C for 10 days) did not induce an increase in WAT preadipocytes. 3-adrenoceptor-knockout mice had a blunted brown adipocyte occurrence upon cold acclimatization. Administration of the 3-adrenoceptor agonist CL316,243 induced the occurrence of brown adipocytes, with the typical morphological features found after cold acclimatization. In contrast, administration of the 1-adrenoceptor agonist xamoterol increased only the number of preadipocytes. These findings indicate that transdifferentiation depends on 3-adrenoceptor activation, whereas preadipocyte recruitment is mediated by 1-adrenoceptor. RT-qPCR experiments disclosed that cold exposure induced enhanced expression of the thermogenic genes and of genes expressed selectively in brown adipose tissue (iBAT) and in both interscapular BAT and WAT. 3-adrenoceptor suppression blunted their expression only in WAT. Furthermore, cold acclimatization induced an increased WAT expression of the gene coding for C/EBP (an antimitotic protein), whereas Ccna1 expression (related to cell proliferation) was unchanged. Overall, our data strongly suggest that the cold-induced emergence of brown adipocytes in WAT predominantly reflects 3-adrenoceptor-mediated transdifferentiation.openBarbatelli G; Murano I; Madsen L; Hao Q; Jimenez M; Kristiansen K; Giacobino JP; De Matteis R; Cinti S.Barbatelli, G; Murano, I; Madsen, L; Hao, Q; Jimenez, M; Kristiansen, K; Giacobino, Jp; DE MATTEIS, Rita; Cinti, S

β-Adrenoceptor Signaling Networks in Adipocytes for Recruiting Stored Fat and Energy Expenditure

The adipocyte is like a bank: a place to store excess (caloric) cash in times of plenty, and from which one can withdraw savings during “lean times.” The β-adrenoceptors (βAR) are the gateways to this mobilization of fat to be consumed in other tissues. This review discusses the βAR signaling pathway(s) in white and brown adipocytes. Studies in rodent models show that brown adipocytes nestled with white fat depots correlate with and are considered a key enabling factor in resistance to diet-induced obesity. Since it is now recognized that adult humans have brown adipocytes, knowing the steps in these signaling pathways may provide the opportunity to manipulate adipocytes to be net consumers of energy

Uncoupling Protein 1 of Brown Adipocytes, the Only Uncoupler: A Historical Perspective

Uncoupling protein 1 (UCP1), is a unique mitochondrial membranous protein devoted to adaptive thermogenesis, a specialized function performed by brown adipocytes. Whereas the family of mitochondrial metabolite carriers comprises ∼40 members, UCP1 is the only memberable to translocate protons through the inner membrane of brown adipocyte mitochondria. By this process, UCP1 uncouples respiration from ATP synthesis and therefore provokes energy dissipation in the form of heat while, also stimulating high levels of fatty acid oxidation. UCP1 homologs were identified but they are biochemically and physiologically different from UCP1. Thirty five years after its identification, UCP1 still appears as a fascinating component. The recent renewal of the interest in human brown adipose tissue makes UCP1 as a potential target for strategies of treatment of metabolic disorders

Presence of the brown fat-specific mitochondrial uncoupling protein and iodothyronine 5'-deiodinase activity in subcutaneous adipose tissue of neonatal lambs

AbstractSubcutaneous adipose tissue of neonatal lambs has been examined for the presence of markers diagnostic of thermogenic brown fat. Uncoupling protein, uncoupling protein mRNA, and iodothyronine 5'-deiodinase activity were each detected in subcutaneous adipose tissue, as well as in the major internal fat depot (perirenal), of newborn lambs. These brown fat markers were not present, however, in adipose tissue of adult sheep. It is concluded that subcutaneous fat in newborn lambs is functionally ‘brown’, and similar to the internal fat; subcutaneous and internal adipose tissues follow a similar developmental path - from ‘brown’ to ‘white’

Retinoic acid has different effects on UCP1 expression in mouse and human adipocytes

BACKGROUND: Increased adipose thermogenesis is being considered as a strategy aimed at preventing or reversing obesity. Thus, regulation of the uncoupling protein 1 (UCP1) gene in human adipocytes is of significant interest. Retinoic acid (RA), the carboxylic acid form of vitamin A, displays agonist activity toward several nuclear hormone receptors, including RA receptors (RARs) and peroxisome proliferator-activated receptor δ (PPARδ). Moreover, RA is a potent positive regulator of UCP1 expression in mouse adipocytes. RESULTS: The effects of all-trans RA (ATRA) on UCP1 gene expression in models of mouse and human adipocyte differentiation were investigated. ATRA induced UCP1 expression in all mouse white and brown adipocytes, but inhibited or had no effect on UCP1 expression in human adipocyte cell lines and primary human white adipocytes. Experiments with various RAR agonists and a RAR antagonist in mouse cells demonstrated that the stimulatory effect of ATRA on UCP1 gene expression was indeed mediated by RARs. Consistently, a PPARδ agonist was without effect. Moreover, the ATRA-mediated induction of UCP1 expression in mouse adipocytes was independent of PPARγ coactivator-1α. CONCLUSIONS: UCP1 expression is differently affected by ATRA in mouse and human adipocytes. ATRA induces UCP1 expression in mouse adipocytes through activation of RARs, whereas expression of UCP1 in human adipocytes is not increased by exposure to ATRA