Summary Nutritional and pharmacological stimuli can dramatically alter the cellular phenotypes in white adipose tissue (WAT). Utilizing genetic lineage tracing techniques, we demonstrate that brown adipocytes (BA) that are induced by β3-adrenergic receptor activation in abdominal WAT arise from the proliferation and differentiation of cells expressing platelet-derived growth factor receptor alpha (PDGFRα), CD34 and Sca1 (PDGFRα+ cells). PDGFRα+ cells have a unique morphology in which extended processes contact multiple cells in the tissue microenvironment. Surprisingly, these cells also give rise to white adipocytes (WA) that can comprise up to 25% of total fat cells in abdominal fat pads following 8 weeks of high fat feeding. Isolated PDGFRα+ cells differentiated into both BA and white adipocytes (WA) in vitro, and generated WA after transplantation in vivo. The identification of PDGFRα+ cells as bipotential adipocyte progenitors will enable further investigation of mechanisms that promote therapeutic cellular remodeling in adult WAT.

Mitochondrial uncoupling protein 1 (UCP1) is enriched within interscapular brown adipose tissue (iBAT) and beige (also known as brite) adipose tissue 1,2 , but its thermogenic potential is reduced with obesity and type 2 diabetes 3-5 for reasons that are not understood. Serotonin (5-hydroxytryptamine, 5-HT) is a highly conserved biogenic amine that resides in non-neuronal and neuronal tissues that are specifically regulated via tryptophan hydroxylase 1 (Tph1) and Tph2, respectively 6-8 . Recent findings suggest that increased peripheral serotonin 9 and polymorphisms in TPH1 are associated with obesity 10 ; however, whether this is directly related to reduced BAT Reprints and permissions information is available online at

SUMMARY Brown (BAT) and white (WAT) adipose tissues play distinct roles in maintaining whole-body energy homeostasis, and their dysfunction can contribute to non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. The AMP-activated protein kinase (AMPK) is a cellular energy sensor, but its role in regulating BAT and WAT metabolism is unclear. We generated an inducible model for deletion of the two AMPK β subunits in adipocytes (iβ1β2AKO) and found that iβ1β2AKO mice were cold intolerant and resistant to β-adrenergic activation of BAT and beiging of WAT. BAT from iβ1β2AKO mice had impairments in mitochondrial structure, function, and markers of mitophagy. In response to a high-fat diet, iβ1β2AKO mice more rapidly developed liver steatosis as well as glucose and insulin intolerance. Thus, AMPK in adipocytes is vital for maintaining mitochondrial integrity, responding to pharmacological agents and thermal stress, and protecting against nutrient-overload-induced NAFLD and insulin resistance.

This article is available online at http://www.jlr.org Classic interscapular brown adipose tissue (BAT) is a thermogenic organ that has a high capacity for uncoupled oxidative metabolism ( 1 ). In contrast, white adipose tissue (WAT) has low oxidative capacity because its main function under normal conditions is to store excess energy as TGs. However, chronic stimulation by ␤ 3-adrenergic receptors ( ␤ 3-ARs) expands the oxidative capacity of WAT and converts it into a tissue resembling BAT. This phenomenon has been termed "browning" of white fat ( 2-4 ) and is marked by increased expression of oxidative genes, induction of uncoupling protein 1 (UCP1), and activation of oxidative metabolism ( 5 ). Importantly, lipolysis plays a central role in the catabolic activity of BAT and WAT. Acutely, mobilized FAs uncouple oxidative phosphorylation and provide fuel that supports both coupled and uncoupled respiration ( 6 ). Lipolysis also provides ligands for PPAR ␣ , which plays a central role in catabolic remodeling of WAT by upregulating oxidative metabolism and limiting FA-induced infl ammation ( 7,8 ). Indeed, several recent studies have demonstrated the importance of lipolysis in providing ligands for activation of PPAR target genes in BAT ( 9, 10 ), heart ( 11 ), liver ( 12, 13 ), and pancreatic ␤ cells ( 14 ).Abstract Chronic activation of ␤ 3-adrenergic receptors ( ␤ 3-ARs) expands the catabolic activity of both brown and white adipose tissue by engaging uncoupling protein 1 (UCP1)-dependent and UCP1-independent processes. The present work examined de novo lipogenesis (DNL) and TG/glycerol dynamics in classic brown, subcutaneous "beige," and classic white adipose tissues during sustained ␤ 3-AR activation by CL 316,243 (CL) and also addressed the contribution of TG hydrolysis to these dynamics. CL treatment for 7 days dramatically increased DNL and TG turnover similarly in all adipose depots, despite great differences in UCP1 abundance. Increased lipid turnover was accompanied by the simultaneous upregulation of genes involved in FAS, glycerol metabolism, and FA oxidation. Inducible, adipocyte-specifi c deletion of adipose TG lipase (ATGL), the rate-limiting enzyme for lipolysis, demonstrates that TG hydrolysis is required for CL-induced increases in DNL, TG turnover, and mitochondrial electron transport in all depots. Interestingly, the effect of ATGL deletion on induction of specifi c genes involved in FA oxidation and synthesis varied among fat depots. Overall, these studies indicate that FAS and FA oxidation are tightly coupled in adipose tissues during chronic adrenergic activation, and this effect critically depends on the activity of adipocyte ATGL. -

Regulation of triglyceride storage and mobilization is critically dependent on the subcellular targeting and trafficking of specific proteins. Recent work demonstrates that this trafficking involves scaffold proteins of the perilipin (Plin) 2 family, including those that are ubiquitously expressed, such as Plin2 (adipose differentiation-related protein) and Plin3 (tail-interacting protein 47, TIP47), and those with restricted expression, such as Plin1 (perilipin) and Plin5 (muscle lipid droplet protein) that appear to have specialized functions (1). Although each Plin homolog has a conserved Plin domain (pfam 03036), amino acid sequences of family members diverge widely outside of this domain (2). Nonetheless, the sequences of individual orthologs are well conserved in mammals and suggest that important functions might be mediated by sequences outside of the Plin domain.We have been investigating how Plin family members organize and regulate the trafficking of lipolytic effector proteins and have focused on Plin1 and Plin5 (3-6). Plin1 is expressed almost exclusively in adipose tissues and plays a central role in the storage of triglyceride and in the rapid mobilization of fatty acids by activators of protein kinase A (1). Recent work indicates that one means by which Plin1 regulates triglyceride storage and mobilization is by controlling the availability of ␣-␤-hydrolase domain-containing 5 (Abhd5), a potent activator of adipose triglyceride lipase (Atgl) (4).In contrast, Plin5 is highly expressed in tissues that have high rates of fatty acid oxidation, such as heart, skeletal muscle, and liver (7,8). Interestingly, expression of Plin5 promotes both triglyceride storage and fatty acid oxidation. Plin5 expression is up-regulated by peroxisome proliferator-activated receptor ␣, and this regulation appears to be part of an expression program that shifts the metabolism of cells from fatty acid storage to oxidation (7).Lipolysis occurs on the surface of intracellular lipid droplets, and several lines of evidence indicate that droplet targeting is critical to the cellular function of Abhd5 and Atgl (9, 10). Abhd5 is targeted to lipid droplets via direct interactions with Plin1 and Plin5 (5, 10, 11). However, unlike Plin1, Plin5 expression promotes the colocalization and interaction of Abhd5 and Atgl in unstimulated cells, which facilitates lipolysis (3-5). It is not known how Plin5 coordinates the interaction of Atgl and Abhd5. On the one hand, Plin5 could bind Atgl5 directly. Alternatively, Atgl might be recruited to the Plin5-containing lipid droplets by virtue of its interaction with Abhd5.In the experiments below, we determined that Atgl interacts with Plin5 but not Plin1. Interestingly, although Plin5 binds both Abhd5 and Atgl, the same Plin5 molecule does not bind both at the same time. Protein complementation experiments, however, indicate that Plin5 forms homo-oligomers and suggest that Abhd5 and Atgl interact as part of this oligomeric structure. Analysis of chimeric and truncated Plin proteins demonstrates ...

Background: Adrenergic activation of brown adipocytes mobilizes fatty acids for oxidation and promotes transcription of oxidative genes. Results: Activation of adipocyte lipases generates agonists of PPAR␣ and PPAR␦ that promote transcription of oxidative genes. Conclusion: Lipolytic products signal via PPAR␣ and PPAR␦. Significance: Lipolytic activation of PPAR␣ and PPAR␦ provides a mechanism for matching oxidative capacity to substrate supply.

Many extracellular signals elicit changes in the actin cytoskeleton, which are mediated through an array of signaling proteins and pathways. One family of proteins that plays a role in regulating actin remodeling in response to cellular signals are the cyclase-associated proteins (CAPs). CAPs are highly conserved monomeric actin binding proteins present in a wide range of organisms including yeast, fly, plants, and mammals. The original CAP was isolated as a component of the Saccharomyces cerevisiae adenylyl cyclase complex that serves as an effector of Ras during nutritional signaling. CAPs are multifunctional molecules that contain domains involved in actin binding, adenylyl cyclase association in yeast, SH3 binding, and oligomerization. Genetic studies in yeast have implicated CAPs in vesicle trafficking and endocytosis. CAPs play a developmental role in multicellular organisms, and studies of Drosophila have illuminated the importance of the actin cytoskeleton during eye development and in establishing oocyte polarity. This review will highlight the critical structural and functional domains of CAPs, describe recent studies that have implied important roles for these proteins in linking cell signaling with actin polymerization, and highlight their roles in vesicle trafficking and development.

Adipose tissue plays an essential role in regulating energy balance through its metabolic, cellular and endocrine functions. Adipose tissue has been historically classified into anabolic white adipose tissue and catabolic brown adipose tissue. An explosion of new data, however, points to the remarkable heterogeneity among the cells types that can become adipocytes, as well as the inherent metabolic plasticity of mature cells. These data indicate that targeting cellular and metabolic plasticity of adipose tissue might provide new avenues for treatment of obesity-related diseases. This review will discuss the developmental origins of adipose tissue, the cellular complexity of adipose tissues, and the identification of progenitors that contribute to adipogenesis throughout development. We will touch upon the pathological remodelling of adipose tissue and discuss how our understanding of adipose tissue remodeling can uncover new therapeutic targets.