BBA - Molecular Basis of Disease (v.1842, #3)

Preface by Jacqueline M. Stephens; Matthew J. Brady (339).

Adipocyte lineages: Tracing back the origins of fat by Joan Sanchez-Gurmaches; David A. Guertin (340-351).
The obesity epidemic has intensified efforts to understand the mechanisms controlling adipose tissue development. Adipose tissue is generally classified as white adipose tissue (WAT), the major energy storing tissue, or brown adipose tissue (BAT), which mediates non-shivering thermogenesis. It is hypothesized that brite adipocytes (brown in white) may represent a third adipocyte class. The recent realization that brown fat exist in adult humans suggests increasing brown fat energy expenditure could be a therapeutic strategy to combat obesity. To understand adipose tissue development, several groups are tracing the origins of mature adipocytes back to their adult precursor and embryonic ancestors. From these studies emerged a model that brown adipocytes originate from a precursor shared with skeletal muscle that expresses Myf5-Cre, while all white adipocytes originate from a Myf5-negative precursors. While this provided a rational explanation to why BAT is more metabolically favorable than WAT, recent work indicates the situation is more complex because subsets of white adipocytes also arise from Myf5-Cre expressing precursors. Lineage tracing studies further suggest that the vasculature may provide a niche supporting both brown and white adipocyte progenitors; however, the identity of the adipocyte progenitor cell is under debate. Differences in origin between adipocytes could explain metabolic heterogeneity between depots and/or influence body fat patterning particularly in lipodystrophy disorders. Here, we discuss recent insights into adipose tissue origins highlighting lineage-tracing studies in mice, how variations in metabolism or signaling between lineages could affect body fat distribution, and the questions that remain unresolved. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
Keywords: White adipose tissue (WAT); Brown adipose tissue (BAT); Brite or beige adipocyte; Myf5; Adipocyte progenitor/precursor; Lipodystrophy;

The differentiation of uncommitted cells into specialized adipocytes occurs through a cascade of transcriptional events culminating in the induction and activation of the nuclear receptor PPARγ, the central coordinator of fat cell function. Since the discovery of PPARγ, two decades ago, our views of how this molecule is activated have been significantly refined. Beyond the cell, we also now know that diverse signals and regulators control PPARγ function in a fat-depot specific manner. The goal of this article is to review the latest in our understanding of the early and late transcriptional events that regulate adipocyte development and their potential impact on energy storage and expenditure in different fat depots. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
Keywords: White adipose depots; Transcriptional regulators; Brown fat; Brite/beige fat cells; PPARgamma; White fat browning;

Adipose tissue plasticity from WAT to BAT and in between by Yun-Hee Lee; Emilio P. Mottillo; James G. Granneman (358-369).
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 remodeling of adipose tissue and discuss how our understanding of adipose tissue remodeling can uncover new therapeutic targets. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
Keywords: Brown adipose tissue; White adipose tissue; Adipocyte progenitor; Beta3-adrenergic receptor;

The recent characterization of brown fat in humans has generated much excitement on the possibility that increased energy expenditure by heat production by this tissue will be able to reduce obesity. This expectation has largely been stimulated by studies with mice that show strong associations between increased brown fat activity and reductions in obesity and insulin resistance. Research in the mouse has been largely based upon the induction or suppression of brown fat and mitochondrial uncoupling protein by genetic methods. The review of this research literature underscores the idea that reductions in obesity in mice are secondary to the primary role of brown adipose tissue in the regulation of body temperature. Given that the variation in brown fat in humans, as detected by PET imaging, is highly associated with administration of adrenergic agonists and reductions in ambient temperature, the effects on obesity in humans may also be secondary to the regulation of body temperature. Induction of thermogenesis by reduced ambient temperature now becomes like muscle and physical activity, another natural method of increased energy expenditure to combat obesity. Furthermore, there is no evidence to indicate that heat production by adrenergic stimulation via cold exposure or drug treatment or the enriched physical environment is restricted to the thermogenic activity of the brown adipocyte.This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
Keywords: Diet induced obesity; Ucp1 −/− mice; Brown adipose tissue and thermogenesis; aP2-Ucp1 transgenic mice; Allelic variation and Ucp1 expression; Muscle and diet-induced thermogenesis;

Sex dimorphism and depot differences in adipose tissue function by Ursula A. White; Yourka D. Tchoukalova (377-392).
Obesity, characterized by excessive adiposity, is a risk factor for many metabolic pathologies, such as type 2 diabetes mellitus (T2DM). Numerous studies have shown that adipose tissue distribution may be a greater predictor of metabolic health. Upper-body fat (visceral and subcutaneous abdominal) is commonly associated with the unfavorable complications of obesity, while lower-body fat (gluteal–femoral) may be protective. Current research investigations are focused on analyzing the metabolic properties of adipose tissue, in order to better understand the mechanisms that regulate fat distribution in both men and women. This review will highlight the adipose tissue depot- and sex-dependent differences in white adipose tissue function, including adipogenesis, adipose tissue developmental patterning, the storage and release of fatty acids, and secretory function. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
Keywords: Adipose tissue; Adipogenesis; Fat distribution; Lipolysis; Fatty acids; Adipokine;

Excess or insufficient lipid storage in white adipose tissue lipid droplets is associated with dyslipidemia, insulin resistance and increased risk for diabetes type 2. Thus, maintenance of adipose lipid droplet growth and function is critical to preserve whole body insulin sensitivity and energy homeostasis. Progress in understanding biology of lipid droplets has underscored the role of proteins that interact with lipid droplets. Here, we review the current knowledge of adipose specific lipid droplet proteins, which share unique functions controlling adipocyte lipid storage, limiting lipid spill-over and lipotoxic effects thought to contribute to disease. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
Keywords: Adipose tissue; Lipid droplet associated protein; Lipid droplet growth; Obesity; Insulin resistance;

New methodologies for studying lipid synthesis and turnover: Looking backwards to enable moving forwards by Stephen F. Previs; David G. McLaren; Sheng-Ping Wang; Steven J. Stout; Haihong Zhou; Kithsiri Herath; Vinit Shah; Paul L. Miller; Larissa Wilsie; Jose Castro-Perez; Douglas G. Johns; Michele A. Cleary; Thomas P. Roddy (402-413).
Our ability to understand the pathogenesis of problems surrounding lipid accretion requires attention towards quantifying lipid kinetics. In addition, studies of metabolic flux should also help unravel mechanisms that lead to imbalances in inter-organ lipid trafficking which contribute to dyslipidemia and/or peripheral lipid accumulation (e.g. hepatic fat deposits). This review aims to outline the development and use of novel methods for studying lipid kinetics in vivo. Although our focus is directed towards some of the approaches that are currently reported in the literature, we include a discussion of the older literature in order to put “new” methods in better perspective and inform readers of valuable historical research. Presumably, future advances in understanding lipid dynamics will benefit from a careful consideration of the past efforts, where possible we have tried to identify seminal papers or those that provide clear data to emphasize essential points. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
Keywords: Stable isotopes; Mass spectrometry; Kinetic biomarker; Dyslipidemia; Cardiovascular disease;

Leptin is hypothesized to function as a negative feedback signal in the regulation of energy balance. It is produced primarily by adipose tissue and circulating concentrations correlate with the size of body fat stores. Administration of exogenous leptin to normal weight, leptin responsive animals inhibits food intake and reduces the size of body fat stores whereas mice that are deficient in either leptin or functional leptin receptors are hyperphagic and obese, consistent with a role for leptin in the control of body weight. This review discusses the effect of leptin on adipocyte metabolism. Because adipocytes express leptin receptors there is the potential for leptin to influence adipocyte metabolism directly. Adipocytes also are insulin responsive and receive sympathetic innervation, therefore leptin can also modify adipocyte metabolism indirectly. Studies published to date suggest that direct activation of adipocyte leptin receptors has little effect on cell metabolism in vivo, but that leptin modifies adipocyte sensitivity to insulin to inhibit lipid accumulation. In vivo administration of leptin leads to a suppression of lipogenesis, an increase in triglyceride hydrolysis and an increase in fatty acid and glucose oxidation. Activation of central leptin receptors also contributes to the development of a catabolic state in adipocytes, but this may vary between different fat depots. Leptin reduces the size of white fat depots by inhibiting cell proliferation both through induction of inhibitory circulating factors and by contributing to sympathetic tone which suppresses adipocyte proliferation. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
Keywords: Leptin receptor; Lipolysis; Lipogenesis; Sympathetic nervous system; Insulin;

Systemic regulation of adipose metabolism by Christopher M. Carmean; Ronald N. Cohen; Matthew J. Brady (424-430).
White adipose tissue serves as a critical energy storage depot and endocrine organ. Adipocytes are subject to numerous levels of regulation, including neuronal, endocrine and metabolic. While insulin is the classical endocrine regulator of lipid metabolism in adipose tissue, other important endocrine hormones also control adipose tissue physiology. In this review, we will focus on the contribution of the pituitary in the modulation of adipocyte function, through the direct release of growth hormone as well as via the regulation of the thyroid gland and release of thyroid hormone. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
Keywords: Adipocyte; Pituitary; Lipolysis;

The role of JAK–STAT signaling in adipose tissue function by Allison J. Richard; Jacqueline M. Stephens (431-439).
Adipocytes play important roles in lipid storage, energy homeostasis and whole body insulin sensitivity. The JAK–STAT (Janus Kinase–Signal Transducer and Activator of Transcription) pathway mediates a variety of physiological processes including development, hematopoiesis, and inflammation. Although the JAK–STAT signaling pathway occurs in all cells, this pathway can mediate cell specific responses. Studies in the last two decades have identified hormones and cytokines that activate the JAK–STAT signaling pathway. These cytokines and hormones have profound effects on adipocytes. The content of this review will introduce the types of adipocytes and immune cells that make up adipose tissue, the impact of obesity on adipose cellular composition and function, and the general constituents of the JAK–STAT pathway and how its activators regulate adipose tissue development and physiology. A summary of the identification of STAT target genes in adipocytes reveals how these transcription factors impact various areas of adipocyte metabolism including insulin action, modulation of lipid stores, and glucose homeostasis. Lastly, we will evaluate exciting new data linking the JAK–STAT pathway and brown adipose tissue and consider the future outlook in this area of investigation. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
Keywords: Brown and white adipose; Janus kinase; Immune cell; Cytokine; Tyk2; Obesity;

Orexin modulation of adipose tissue by Claudio E. Perez-Leighton; Charles J. Billington; Catherine M. Kotz (440-445).
The orexins are neuropeptides with critical functions in the central nervous system. These neuropeptides have important roles in energy balance and obesity, and therefore on the accumulation of adipose tissue. Rodents lacking orexins, typically through genetic knockouts, experience increased weight gain and accumulation of adipose tissue. Evidence indicates that the lack of the orexins increase adiposity as a result of decreased energy expenditure, principally through a reduction of physical activity. Different lines of evidence suggest that other mechanisms are likely also in play, and neural influences on both white and brown adipose tissues remain to be fully and functionally defined. In addition, the orexin peptides and their receptors are expressed in adipose tissue, with little available information as to their significance. This review summarizes our current understanding of how the orexin peptides affect adipose tissue. We provide a brief introduction to the physiology of orexins and their effects on white and brown adipose tissues in the context of energy balance. We conclude this review by integrating this information in the context of the known physiology of the orexins. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
Keywords: Brain; Orexin; Adipose tissue; Energy expenditure;

There is increasing evidence showing that inflammation is an important pathogenic mediator of the development of obesity-induced insulin resistance. It is now generally accepted that tissue-resident immune cells play a major role in the regulation of this obesity-induced inflammation. The roles that adipose tissue (AT)-resident immune cells play have been particularly extensively studied. AT contains most types of immune cells and obesity increases their numbers and activation levels, particularly in AT macrophages (ATMs). Other pro-inflammatory cells found in AT include neutrophils, Th1 CD4 T cells, CD8 T cells, B cells, DCs, and mast cells. However, AT also contains anti-inflammatory cells that counter the pro-inflammatory immune cells that are responsible for the obesity-induced inflammation in this tissue. These anti-inflammatory cells include regulatory CD4 T cells (Tregs), Th2 CD4 T cells, and eosinophils. Hence, AT inflammation is shaped by the regulation of pro- and anti-inflammatory immune cell homeostasis, and obesity skews this balance towards a more pro-inflammatory status. Recent genetic studies revealed several molecules that participate in the development of obesity-induced inflammation and insulin resistance. In this review, the cellular and molecular players that participate in the regulation of obesity-induced inflammation and insulin resistance are discussed, with particular attention being placed on the roles of the cellular players in these pathogeneses. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
Keywords: Adipose tissue; Obesity-induced Inflammation; Adipose tissue immune cell; Insulin resistance;

Adipose tissue angiogenesis: Impact on obesity and type-2 diabetes by Silvia Corvera; Olga Gealekman (463-472).
The growth and function of tissues are critically dependent on their vascularization. Adipose tissue is capable of expanding many-fold during adulthood, therefore requiring the formation of new vasculature to supply growing and proliferating adipocytes. The expansion of the vasculature in adipose tissue occurs through angiogenesis, where new blood vessels develop from those pre-existing within the tissue. Inappropriate angiogenesis may underlie adipose tissue dysfunction in obesity, which in turn increases type-2 diabetes risk. In addition, genetic and developmental factors involved in vascular patterning may define the size and expandability of diverse adipose tissue depots, which are also associated with type-2 diabetes risk. Moreover, the adipose tissue vasculature appears to be the niche for pre-adipocyte precursors, and factors that affect angiogenesis may directly impact the generation of new adipocytes. Here we review recent advances on the basic mechanisms of angiogenesis, and on the role of angiogenesis in adipose tissue development and obesity. A substantial amount of data points to a deficit in adipose tissue angiogenesis as a contributing factor to insulin resistance and metabolic disease in obesity. These emerging findings support the concept of the adipose tissue vasculature as a source of new targets for metabolic disease therapies. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
Keywords: Adipocyte; Endothelial; Vascular; Fat; Capillary; Blood vessel;

Deconstructing the roles of glucocorticoids in adipose tissue biology and the development of central obesity by Mi-Jeong Lee; Pornpoj Pramyothin; Kalypso Karastergiou; Susan K. Fried (473-481).
Central obesity is associated with insulin resistance and dyslipidemia. Thus, the mechanisms that control fat distribution and its impact on systemic metabolism have importance for understanding the risk for diabetes and cardiovascular disease. Hypercortisolemia at the systemic (Cushing's syndrome) or local levels (due to adipose-specific overproduction via 11β-hydroxysteroid dehydrogenase 1) results in the preferential expansion of central, especially visceral fat depots. At the same time, peripheral subcutaneous depots can become depleted. The biochemical and molecular mechanisms underlying the depot-specific actions of glucocorticoids (GCs) on adipose tissue function remain poorly understood. GCs exert pleiotropic effects on adipocyte metabolic, endocrine and immune functions, and dampen adipose tissue inflammation. GCs also regulate multiple steps in the process of adipogenesis. Acting synergistically with insulin, GCs increase the expression of numerous genes involved in fat deposition. Variable effects of GC on lipolysis are reported, and GC can improve or impair insulin action depending on the experimental conditions. Thus, the net effect of GC on fat storage appears to depend on the physiologic context. The preferential effects of GC on visceral adipose tissue have been linked to higher cortisol production and glucocorticoid receptor expression, but the molecular details of the depot-dependent actions of GCs are only beginning to be understood. In addition, increasing evidence underlines the importance of circadian variations in GCs in relationship to the timing of meals for determining their anabolic actions on the adipocyte. In summary, although the molecular mechanisms remain to be fully elucidated, there is increasing evidence that GCs have multiple, depot-dependent effects on adipocyte gene expression and metabolism that promote central fat deposition. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
Keywords: Cortisol; Inflammation; Adipokine; Lipogenesis; Lipolysis; 11-beta hydroxysteroid dehydrogenase;

Neural melanocortin receptors in obesity and related metabolic disorders by Clemence Girardet; Andrew A. Butler (482-494).
Obesity is a global health issue, as it is associated with increased risk of developing chronic conditions associated with disorders of metabolism such as type 2 diabetes and cardiovascular disease. A better understanding of how excessive fat accumulation develops and causes diseases of the metabolic syndrome is urgently needed. The hypothalamic melanocortin system is an important point of convergence connecting signals of metabolic status with the neural circuitry that governs appetite and the autonomic and neuroendocrine system controling metabolism. This system has a critical role in the defense of body weight and maintenance of homeostasis. Two neural melanocortin receptors, melanocortin 3 and 4 receptors (MC3R and MC4R), play crucial roles in the regulation of energy balance. Mutations in the MC4R gene are the most common cause of monogenic obesity in humans, and a large literature indicates a role in regulating both energy intake through the control of satiety and energy expenditure. In contrast, MC3Rs have a more subtle role in energy homeostasis. Results from our lab indicate an important role for MC3Rs in synchronizing rhythms in foraging behavior with caloric cues and maintaining metabolic homeostasis during periods of nutrient scarcity. However, while deletion of the Mc3r gene in mice alters nutrient partitioning to favor accumulation of fat mass no obvious role for MC3R haploinsufficiency in human obesity has been reported. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
Keywords: Melanocortin receptor; Nervous system; Metabolic homeostasis; Obesity; Genetic model; Human;

Mammalian embryos have evolved to adjust their organ and tissue development in response to an atypical environment. This adaptation, called phenotypic plasticity, allows the organism to thrive in the anticipated environment in which the fetus will emerge. Barker and colleagues proposed that if the environment in which the fetus emerges differs from that in which it develops, phenotypic plasticity may provide an underlying mechanism for disease. Epidemiological studies have shown that humans born small- or large-for-gestational-age, have a higher likelihood of developing obesity as adults. The amount and quality of food that the mother consumes during gestation influences birth weight, and therefore susceptibility of progeny to disease in later life. Studies in experimental animals support these observations, and find that obesity occurs as a result of maternal nutrient-restriction during gestation, followed by rapid compensatory growth associated with ad libitum food consumption. Therefore, obesity associated with maternal nutritional restriction has a developmental origin. Based on this phenomenon, one might predict that gestational exposure to a westernized diet would protect against future obesity in offspring. However, evidence from experimental models indicates that, like maternal dietary restriction, maternal consumption of a westernized diet during gestation and lactation interacts with an adult obesogenic diet to induce further obesity. Mechanistically, restriction of nutrients or consumption of a high fat diet during gestation may promote obesity in progeny by altering hypothalamic neuropeptide production and thereby increasing hyperphagia in offspring. In addition to changes in food intake these animals may also direct energy from muscle toward storage in adipose tissue. Surprisingly, generational inheritance studies in rodents have further indicated that effects on body length, body weight, and glucose tolerance appear to be propagated to subsequent generations. Together, the findings discussed herein highlight the concept that maternal nutrition contributes to a legacy of obesity. Thus, ensuring adequate supplies of a complete and balanced diet during and after pregnancy should be a priority for public health worldwide. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
Keywords: Maternal health; Obesity; Nutrition;

Animal models of in utero exposure to a high fat diet: A review by Lyda Williams; Yoshinori Seki; Patricia M. Vuguin; Maureen J. Charron (507-519).
The incidence of metabolic disease, including type 2 diabetes and obesity, has increased to epidemic levels in recent years. A growing body of evidence suggests that the intrauterine environment plays a key role in the development of metabolic disease in offspring. Among other perturbations in early life, alteration in the provision of nutrients has profound and lasting effects on the long term health and well being of offspring. Rodent and non-human primate models provide a means to understand the underlying mechanisms of this programming effect. These different models demonstrate converging effects of a maternal high fat diet on insulin and glucose metabolism, energy balance, cardiovascular function and adiposity in offspring. Furthermore, evidence suggests that the early life environment can result in epigenetic changes that set the stage for alterations in key pathways of metabolism that lead to type 2 diabetes or obesity. Identifying and understanding the causal factors responsible for this metabolic dysregulation is vital to curtailing these epidemics. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
Keywords: In utero programming; High fat diet; Diabetes; Obesity; Metabolic disease;

Adipocytes under assault: Environmental disruption of adipose physiology by Shane M. Regnier; Robert M. Sargis (520-533).
The burgeoning obesity epidemic has placed enormous strains on individual and societal health mandating a careful search for pathogenic factors, including the contributions made by endocrine disrupting chemicals (EDCs). In addition to evidence that some exogenous chemicals have the capacity to modulate classical hormonal signaling axes, there is mounting evidence that several EDCs can also disrupt metabolic pathways and alter energy homeostasis. Adipose tissue appears to be a particularly important target of these metabolic disruptions. A diverse array of compounds has been shown to alter adipocyte differentiation, and several EDCs have been shown to modulate adipocyte physiology, including adipocytic insulin action and adipokine secretion. This rapidly emerging evidence demonstrating that environmental contaminants alter adipocyte function emphasizes the potential role that disruption of adipose physiology by EDCs may play in the global epidemic of metabolic disease. Further work is required to better characterize the molecular targets responsible for mediating the effects of EDCs on adipose tissue. Improved understanding of the precise signaling pathways altered by exposure to environmental contaminants will enhance our understanding of which chemicals pose a threat to metabolic health and how those compounds synergize with lifestyle factors to promote obesity and its associated complications. This knowledge may also improve our capacity to predict which synthetic compounds may alter energy homeostasis before they are released into the environment while also providing critical evidentiary support for efforts to restrict the production and use of chemicals that pose the greatest threat to human metabolic health. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
Keywords: Adipocyte differentiation; Adipose tissue; Endocrine disruptor; EDCs; Metabolism; Pollution;