The composition,function, and regulation of adipose stem and progenitor cells

White adipose tissue (WAT) is a highly plastic organ that plays a central role in regulating whole-body energy metabolism. Adipose stem and progenitor cells (ASPCs) are essential components of the stromal vascular fraction (SVF) of adipose tissue. They give rise to mature adipocytes and play a critical role in maintaining adipose tissue function. However, the molecular heterogeneity and functional diversity of ASPCs are still poorly understood. Recently, single-cell RNA sequencing (scRNA-seq) analysis has identified distinct subtypes of ASPCs in murine and human adipose tissues, providing new insights into the cellular complexity of ASPCs among multiple fat depots. This review summarizes the current knowledge on ASPC populations, including their markers, functions, and regulatory mechanisms. Targeting one or several of these cell populations may ameliorate metabolic disorders by promoting adaptive hyperplastic adipose growth.     

Metabolic Dysregulation and Adipose Tissue Fibrosis: Role of Collagen VI

Adipocytes are embedded in a unique extracellular matrix whose main function is to provide mechanical support, in addition to participating in a variety of signaling events. During adipose tissue expansion, the extracellular matrix requires remodeling to accommodate adipocyte growth. Here, we demonstrate a general upregulation of several extracellular matrix components in adipose tissue in the diabetic state, therefore implicating “adipose tissue fibrosis” as a hallmark of metabolically challenged adipocytes. Collagen VI is a highly enriched extracellular matrix component of adipose tissue. The absence of collagen VI results in the uninhibited expansion of individual adipocytes and is paradoxically associated with substantial improvements in whole-body energy homeostasis, both with high-fat diet exposure and in the ob/ob background. Collectively, our data suggest that weakening the extracellular scaffold of adipocytes enables their stress-free expansion during states of positive energy balance, which is consequently associated with an improved inflammatory profile. Therefore, the disproportionate accumulation of extracellular matrix components in adipose tissue may not be merely an epiphenomenon of metabolically challenging conditions but may also directly contribute to a failure to expand adipose tissue mass during states of excess caloric intake.Adipose tissue is a key regulator of systemic energy homeostasis. The physiological state of adipose tissue is driven by cell-autonomous processes within the adipocyte. In addition to this, the adipocyte itself is subject to major modifications by other cell types that infiltrate adipose tissue, such as macrophages and vascular cells; moreover, adipocytes can be markedly influenced by several hormones and cytokines that circulate systemically.Although all these cellular interactions have been the subject of extensive studies in numerous laboratories, the extracellular matrix of adipose tissue has received limited attention to date, despite evidence suggesting that it is a functionally relevant constituent of adipose tissue physiology.It is currently unknown what consequential effects metabolic stress exerts on the extracellular matrix and vice versa. In other words, what is the impact of dysregulation of the extracellular constituents of adipose tissue on the systemic metabolic state? Here, we approach this subject from two different perspectives. We first assessed the overall level of extracellular matrix components under different metabolic conditions and established that the extracellular constituents are globally upregulated during metabolically challenging conditions. We then selected a specific member of the collagen family, collagen VI (exhibiting predominant expression in adipose tissue), and utilized a genetic model of collagen VI disruption to investigate the effects of disruption of the extracellular matrix of adipose tissue. Remarkably, our studies demonstrated that such weakening of adipose tissue extracellular matrix results in considerable improvement of the metabolic phenotype in the context of both a high-fat diet and a challenge with the ob/ob mutation.Our observations highlight the extracellular matrix of adipose tissue as an important and novel site of modulation of systemic metabolism. Obese adipose tissue displays hallmarks similar to other fibrotic tissues, such as the liver; this suggests that specific constituents of this normally rather rigid extracellular matrix environment may provide possible targets for pharmacological intervention for the treatment of metabolic disorders.     

Adipose tissue plasticity from WAT to BAT and in between

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.     

Proteomic characterization of adipose tissue constituents, a necessary step for understanding adipose tissue complexity

The original concept of adipose tissue as an inert storage depot for the excess of energy has evolved over the last years and it is now considered as one of the most important organs regulating body homeostasis. This conceptual change has been supported by the demonstration that adipose tissue serves as a major endocrine organ, producing a wide variety of bioactive molecules, collectively termed adipokines, with endocrine, paracrine and autocrine activities. Adipose tissue is indeed a complex organ wherein mature adipocytes coexist with the various cell types comprising the stromal-vascular fraction (SVF), including preadipocytes, adipose-derived stem cells, perivascular cells, and blood cells. It is known that not only mature adipocytes but also the components of SVF produce adipokines. Furthermore, adipokine production, proliferative and metabolic activities and response to regulatory signals (i.e. insulin, catecholamines) differ between the different fat depots, which have been proposed to underlie their distinct association to specific diseases. Herein, we discuss the recent proteomic studies on adipose tissue focused on the analysis of the separate cellular components and their secretory products, with the aim of identifying the basic features and the contribution of each component to different adipose tissue-associated pathologies.     

Neuroadipology: A novel component of neuroendocrinology

Adipose tissue is a dynamic endocrine and paracrine organ producing a large number of signalling proteins collectively termed adipokines. Some of them are mediators in the cross‐talk between adipose tissue and the brain in regulating food intake and energy homoeostasis. However, the hypothalamus is not the only brain target for adipokines, and food intake is not the only biological effect of these signals. Rather, some adipokines support various cognitive functions and exert neurotrophic activity. Current data on adipose‐derived neuropeptides, neurotrophic factors, pituitary hormones and hypothalamic releasing factors is highlighted in this review. We propose that adipose tissue is a member of the diffuse neuroendocrine system. Cumulatively, this is conceptualized as neuroadipology, a new example of a link between neurobiology and other topics, such as neuroimmunology and neuroendocrinology. Because adipose tissue is a bona fide endocrine organ, neuroadipology may be considered a new discipline in neuroendocrinology. It may have a wide‐ranging potential within a variety of neuronal and metabolic functions in health and disease.     

Wu-Mei-Wan prevents high-fat diet-induced obesity by reducing white adipose tissue and enhancing brown adipose tissue function

BackgroundWu-Mei-Wan, a classic traditional Chinese herb medicine, is one of the most important formulations to treat digestive diseases from ancient times to the present. Our previous study showed that WMW treatment can prevent T2DM in db/db mice, which motivating the application of WMW on metabolic disorders.PurposeObesity and its comorbid diseases have increased dramatically and are now a worldwide health problem. There is still a lack of satisfactory treatment strategies for obesity. This work was designed to assess the effect and related mechanism of WMW on high fat diet (HFD)-induced obese mice model.MethodsObese mice were induced by HFD. Thetherapeutic effect of WMW were analyzed by examining body and adipose tissue weight, metabolic profile and energy expenditure. Adipose tissue phenotype was determined by histological staining and the mitochondrial content was examined by transmission electron microscopy (TEM). Immunohistochemical and immunofluorescence staining, RT-qPCR and Western blot analysis were used to evaluate expression of key molecules in adipose tissue.ResultsWMW treatment significantly protects HFD-induced obesity. Here we showed that WMW limits weight gain, improves metabolic profile and increases energy expenditure. WMW inhibits the hypertrophy and hyperplasia of white adipocytes, the mechanism involving the inhibition of TLR3/IL-6/JAK1/STAT3 pathway. In brown adipose tissue (BAT), WMW promotes thermogenicprogramme without affecting cell proliferation. The activated BMP7/ Smad1/5/9 pathway is considered to be one of the explanations for the effect of WMW on BAT.ConclusionOur results suggested that WMW can prevent obesity and its underlying mechanisms are associated with reducing white adipose tissue and enhancing brown adipose tissue function.     

Therapeutic applications of conditioned medium from adipose tissue

For the past number of decades, adipose tissue has attracted significant interest due to its complicated composition and versatile functions. Adipose tissue is no longer considered to be just an energy‐storing fat pad, but is also a key ring player in interaction networks between various organs and tissues. A wide range of factors released by adipose tissue are responsible for regulation of adipose tissue and other distant target tissues and cells, such as kidneys, skeletal muscle, the cardiovascular system and the immune system, in an auto‐/paracrine manner. A mixture of bioactive molecules makes up the conditioned medium of adipose tissue. The beneficial role played by these bioactive molecules in angiogenesis, wound healing, tissue regeneration and immunomodulation has been demonstrated by various studies. Study of this conditioned medium helps deepen our understanding of underlying mechanisms and broadens the potential for therapeutic applications. In this review, we have aimed to improve fundamental understanding of conditioned medium from adipose tissue and to summarize recent efforts to study its therapeutic applications.     

Lipolysis: pathway under construction

PURPOSE OF REVIEW: The lipolytic catabolism of stored fat in adipose tissue supplies tissues with fatty acids as metabolites and energy substrates during times of food deprivation. This review focuses on the function of recently discovered enzymes in adipose tissue lipolysis and fatty acid mobilization. RECENT FINDINGS: The characterization of hormone-sensitive lipase-deficient mice provided compelling evidence that hormone-sensitive lipase is not uniquely responsible for the hydrolysis of triacylglycerols and diacylglycerols of stored fat. Recently, three different laboratories independently discovered a novel enzyme that also acts in this capacity. We named the enzyme 'adipose triglyceride lipase' in accordance with its predominant expression in adipose tissue, its high substrate specificity for triacylglycerols, and its function in the lipolytic mobilization of fatty acids. Two other research groups showed that adipose triglyceride lipase (named desnutrin and Ca-independent phospholipase A2zeta, respectively) is regulated by the nutritional status and that it might exert acyl-transacylase activity in addition to its activity as triacylglycerol hydrolase. Adipose triglyceride lipase represents a novel type of 'patatin domain-containing' triacylglycerol hydrolase that is more closely related to plant lipases than to other known mammalian metabolic triacylglycerol hydrolases. SUMMARY: Although the regulation of adipose triglyceride lipase and its physiological function remain to be determined in mouse lines that lack or overexpress the enzyme, present data permit the conclusion that adipose triglyceride lipase is involved in the cellular mobilization of fatty acids, and they require a revision of the concept that hormone-sensitive lipase is the only enzyme involved in the lipolysis of adipose tissue triglycerides.     

Role of obesity-associated dysfunctional adipose tissue in cancer: a molecular nutrition approach

Obesity is a complex disease caused by the interaction of a myriad of genetic, dietary, lifestyle and environmental factors, which favors a chronic positive energy balance, leading to increased body fat mass. There is emerging evidence of a strong association between obesity and an increased risk of cancer. However, the mechanisms linking both diseases are not fully understood. Here, we analyze the current knowledge about the potential contribution that expanding adipose tissue in obesity could make to the development of cancer via dysregulated secretion of pro-inflammatory cytokines, chemokines and adipokines such as TNF-α, IL-6, leptin, adiponectin, visfatin and PAI-1. Dietary factors play an important role in the risk of suffering obesity and cancer. The identification of bioactive dietary factors or substances that affect some of the components of energy balance to prevent/reduce weight gain as well as cancer is a promising avenue of research. This article reviews the beneficial effects of some bioactive food molecules (n-3 PUFA, CLA, resveratrol and lipoic acid) in energy metabolism and cancer, focusing on the molecular mechanisms involved, which may provide new therapeutic targets in obesity and cancer.     

Adipocyte lineages: Tracing back the origins of fat

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.     

Adipose tissue dysfunction in cancer cachexia

Cancer cachexia is a complex disorder that is driven by inflammation and metabolic imbalances, resulting in extreme weight loss. Adipose tissue, a main player in cancer cachexia, is an essential metabolic and secretory organ consisting of both white adipose tissue (WAT) and brown adipose tissue. Its secretory products, including adipokines and cytokines, affect a wide variety of central and peripheral organs, such as the skeletal muscle, brain, pancreas, and liver. Therefore, a combination of metabolic alterations, and systemic inflammation dysregulation of both anti-inflammatory and proinflammatory modulators contribute toward adipose tissue wasting in cancer cachexia. Growing evidence suggests that, during cancer cachexia, WAT undergoes a browning process, resulting in increased lipid mobilization and energy expenditure. In this review, we have summarized the characteristics of cancer cachexia and WAT browning. Furthermore, this review describes how adipose tissue becomes inflamed in cancer, shedding light on the combinatorial action of multiple secreted macromolecules, cytokines, hormones, and tumor mediators on adipose tissue dysfunction. We also highlight the inflammatory responses, energy utilization defects, and molecular mechanisms underlying the WAT dysfunction and browning in cancer cachexia. Further, the actual mechanisms behind the loss of adipose tissue are unknown, but have been attributed to increased adipocyte lipolysis, systemic inflammation, and apoptosis or reduced lipogenesis. The understanding of adipose tissue dysfunction in cancer cachexia will hopefully promote the development of new therapeutic approaches to prevent or treat this wasting syndrome.     

Adipose tissue angiogenesis: Impact on obesity and type-2 diabetes

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.     

Sex dimorphism and depot differences in adipose tissue function

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.     

Adipose tissue: between the extremes

Adipose tissue represents a critical component in healthy energy homeostasis. It fulfills important roles in whole‐body lipid handling, serves as the body's major energy storage compartment and insulation barrier, and secretes numerous endocrine mediators such as adipokines or lipokines. As a consequence, dysfunction of these processes in adipose tissue compartments is tightly linked to severe metabolic disorders, including obesity, metabolic syndrome, lipodystrophy, and cachexia. While numerous studies have addressed causes and consequences of obesity‐related adipose tissue hypertrophy and hyperplasia for health, critical pathways and mechanisms in (involuntary) adipose tissue loss as well as its systemic metabolic consequences are far less understood. In this review, we discuss the current understanding of conditions of adipose tissue wasting and review microenvironmental determinants of adipocyte (dys)function in related pathophysiologies.     

Adipokines in inflammation and metabolic disease

The worldwide epidemic of obesity has brought considerable attention to research aimed at understanding the biology of adipocytes (fat cells) and the events occurring in adipose tissue (fat) and in the bodies of obese individuals. Accumulating evidence indicates that obesity causes chronic low-grade inflammation and that this contributes to systemic metabolic dysfunction that is associated with obesity-linked disorders. Adipose tissue functions as a key endocrine organ by releasing multiple bioactive substances, known as adipose-derived secreted factors or adipokines, that have pro-inflammatory or anti-inflammatory activities. Dysregulated production or secretion of these adipokines owing to adipose tissue dysfunction can contribute to the pathogenesis of obesity-linked complications. In this Review, we focus on the role of adipokines in inflammatory responses and discuss their potential as regulators of metabolic function.