The ability of mammals to resist body fat accumulation is linked to their ability to expand the number and activity of "brown adipocytes" within white fat depots. Activation of β-adrenergic receptors (β-ARs) can induce a functional "brown-like" adipocyte phenotype. As cardiac natriuretic peptides (NPs) and β-AR agonists are similarly potent at stimulating lipolysis in human adipocytes, we investigated whether NPs could induce human and mouse adipocytes to acquire brown adipocyte features, including a capacity for thermogenic energy expenditure mediated by uncoupling protein 1 (UCP1). In human adipocytes, atrial NP (ANP) and ventricular NP (BNP) activated PPARγ coactivator-1α (PGC-1α) and UCP1 expression, induced mitochondriogenesis, and increased uncoupled and total respiration. At low concentrations, ANP and β-AR agonists additively enhanced expression of brown fat and mitochondrial markers in a p38 MAPK-dependent manner. Mice exposed to cold temperatures had increased levels of circulating NPs as well as higher expression of NP signaling receptor and lower expression of the NP clearance receptor (Nprc) in brown adipose tissue (BAT) and white adipose tissue (WAT). NPR-C -/-mice had markedly smaller WAT and BAT depots but higher expression of thermogenic genes such as Ucp1. Infusion of BNP into mice robustly increased Ucp1 and Pgc-1α expression in WAT and BAT, with corresponding elevation of respiration and energy expenditure. These results suggest that NPs promote "browning" of white adipocytes to increase energy expenditure, defining the heart as a central regulator of adipose tissue biology. IntroductionThe cardiac natriuretic peptides (NPs), atrial NP (ANP) and its ventricular companion (BNP), are key hormones in fluid and hemodynamic homeostasis. Their actions are mediated by binding to NP receptor A (NPRA), whose intracellular domain possesses guanylyl cyclase activity to generate the second messenger cGMP (1, 2). Another member of the NP receptor family (NPRC, which is referred to as the clearance receptor) also binds ANP and BNP to remove them from circulation (3). Almost 2 decades ago, NP receptors were unexpectedly found to be expressed in adipose tissue of both rats (4) and humans (5), and, interestingly, levels of NPRC in adipose tissue were found to be sharply decreased by fasting in rats (6). Together, these were some of the first results to suggest that perhaps cardiac NPs have a metabolic role in adipocytes, including a putative role for adipose tissue in the clearance of these peptides from the circulation (7).ANP was subsequently shown to increase lipolysis in human adipocytes, with a potency similar to that of catecholamines (8), which are the well-established physiological pathway controlling lipolysis through activation of the β-adrenergic receptors (β-ARs). Interestingly, the ability of NPs to stimulate lipolysis was reported to be primate specific and apparently absent from rodent adipose tissue (9). To understand this process mechanistically, recall that β-ARs, as the classic stimulator o...

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High fat intake is associated with fat mass gain through fatty acid activation of peroxisome proliferator-activated receptors ␦ and ␥ , which promote adipogenesis. We show herein that, compared to a combination of specific agonists to both receptors or to saturated, monounsaturated, and -3 polyunsaturated fatty acids, arachidonic acid (C20:4, -6) promoted substantially the differentiation of clonal preadipocytes. This effect was blocked by cyclooxygenase inhibitors and mimicked by carbacyclin, suggesting a role for the prostacyclin receptor and activation of the cyclic AMPdependent pathways that regulate the expression of the CCAAT enhancer binding proteins ␤ and ␦ implicated in adipogenesis. During the pregnancy-lactation period, mother mice were fed either a high-fat diet rich in linoleic acid, a precursor of arachidonic acid (LO diet), or the same isocaloric diet enriched in linoleic acid and ␣ -linolenic acid (LO/ LL diet). Body weight from weaning onwards, fat mass, epididymal fat pad weight, and adipocyte size at 8 weeks of age were higher with LO diet than with LO/LL diet. In contrast, prostacyclin receptor-deficient mice fed either diet were similar in this respect, indicating that the prostacyclin signaling contributes to adipose tissue development. These results raise the issue of the high content of linoleic acid of i ) ingested lipids during pregnancy and lactation, and ii ) formula milk and infant foods in relation to the epidemic of childhood obesity. -Massiera, F., P. Saint-Marc, J. Seydoux, T. Murata, T. Kobayashi, S. Narumiya, P. Guesnet, E-Z. Amri, R. Negrel, and G, Ailhaud. Obesity is associated with metabolic disorders such as dyslipidemia, diabetes, and hypertension, and fat mass excess in severe obesities is typically due to an increase in adipocyte size and number. The formation of adipocytes is a critical event, as mature adipocytes do not divide in vivo and do not undergo significant turnover under physiological conditions. The capacity for proliferation of precursor cells and their differentiation into adipocytes is highest at early age and decrease thereafter in humans and rodents. A limited number of hormones can affect the adipose tissue mass and possibly its distribution (1). High dietary fat intake is now recognized to be associated with a gain of fat mass in animals and humans at all ages (2-5). However, the lack of evidence of a general increase in energy intake as fat among youths, despite a striking increase in the prevalence of obesity in industrial and developing countries, may be due in part to decreased physical activity and nonexercise activity thermogenesis (6), but also to the composition of food intake in early life. The long-term relationship between the fatty acid composition of dietary fats and the development of adipose tissue in humans is difficult to assess in contrast to animals. When mother rats were fed a high-fat diet rich in linoleic acid (C18:2, -6) or saturated fatty acids, suckling pups at 17 days of age exhibited hyperplasia or hypertrophy of whi...

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Exposure of preadipocytes to long chain fatty acids induces expression of several gene markers of adipocyte differentiation. This report describes the cloning, from a preadipocyte library, of a cDNA encoding a fatty acid-activated receptor, FAAR. The cDNA had the characteristics and ligand-binding domains of nuclear hormone receptors and encoded a 440 amino acid protein related to peroxisome proliferator-activated receptors, PPAR. The deduced protein sequence was 88% homologous to that of hNUC I, isolated from human osteosarcoma cells. FAAR mRNA was abundant in adipose tissue, intestine, brain, heart, and skeletal muscles and less abundant in kidney, liver, testis, and spleen. The mRNA was undetectable in growing Ob1771 and 3T3-F442A preadipocytes, was strongly induced early during differentiation, and was increased by fatty acid. Transcription assays using hybrid receptor showed strong stimulation by fatty acid and weaker induction by fibrates. Transfection of 3T3-C2 fibroblasts, with a FAAR expression vector, conferred fatty acid inducibility of the adipocyte lipid-binding protein and the fatty acid transporter. Transcriptional induction of these genes exhibited inducer specificity identical to that described in preadipocytes. In summary, the data indicate that FAAR is likely a mediator of fatty acid transcriptional effects in preadipocytes.

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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.

Osteoporosis constitutes a major worldwide public health burden characterized by enhanced skeletal fragility. Bone metabolism is the combination of bone resorption by osteoclasts and bone formation by osteoblasts. Whereas increase in bone resorption is considered as the main contributor of bone loss that may lead to osteoporosis, this loss is accompanied by increased bone marrow adiposity. Osteoblasts and adipocytes share the same precursor cell and an inverse relationship exists between the two lineages. Therefore, identifying signaling pathways that stimulate mesenchymal stem cells osteogenesis at the expense of adipogenesis is of major importance for developing new therapeutic treatments. For this purpose, we identified by transcriptomic analysis the oxytocin receptor pathway as a potential regulator of the osteoblast/adipocyte balance of human multipotent adipose-derived stem (hMADS) cells. Both oxytocin (OT) and carbetocin (a stable OT analogue) negatively modulate adipogenesis while promoting osteogenesis in both hMADS cells and human bone marrow mesenchymal stromal cells. Consistent with these observations, ovariectomized (OVX) mice and rats, which become osteoporotic and exhibit disequilibrium of this balance, have significant decreased OT levels compared to sham-operated controls. Subcutaneous OT injection reverses bone loss in OVX mice and reduces marrow adiposity. Clinically, plasma OT levels are significantly lower in postmenopausal women developing osteoporosis than in their healthy counterparts. Taken together, these results suggest that plasma OT levels represent a novel diagnostic marker for osteoporosis and that OT administration holds promise as a potential therapy for this disease.