BBA - Molecular and Cell Biology of Lipids (v.1801, #3)

Special issue on lipotoxicity by A. Vidal-Puig; Roger H. Unger (207-208).

Lipid homeostasis, lipotoxicity and the metabolic syndrome by Roger H. Unger; Gregory O. Clark; Philipp E. Scherer; Lelio Orci (209-214).
In the 20th century industrialized nations have become afflicted with an unprecedented pandemic of increased adiposity. In the United States, the epicenter of the epidemic, over 2/3 of the population, is overweight and 1 of every 6 Americans carries the diagnosis of metabolic syndrome. Although genes determine susceptibility to environmental factors, the epidemic is clearly due to increased consumption of calorie-dense, highly lipogenic foods, coupled with a marked decrease in physical exertion resulting from modern technologies. If this lifestyle continues, morbid consequences are virtually inevitable. They include type II diabetes and a cluster of disorders known as “the metabolic syndrome” usually appearing in middle age. The morbid consequences of the chronic caloric surplus are buffered before middle age by the partitioning of these calories as fat in the adipocyte compartment which is specifically designed to store triglycerides. Leptin has been proposed as the major hormonal regulator of the partitioning of surplus calories. However, multiple factors can determine the storage capacity of the fat tissue and when it is exceeded ectopic lipid deposition begins. The organs affected in metabolic syndrome include skeletal muscle, liver, heart and pancreas, which are now known to contain abnormal levels of triglycerides. While neutral fat is probably harmless, it is an index of ectopic lipid overload. Fatty acid derivatives can interfere with the function of the cell and ultimately lead to its demise through lipoapoptosis, the consequences of which are gradual organ failure.
Keywords: Metabolic syndrome; Lipotoxicity; Caloric surplus; Leptin; Apoptosis; Adipocyte;

Looking back over the century long research career of the fruit fly, Drosophila melanogaster has frequently been in the scientific spotlight with respect to fundamental discoveries in biology. The last decade witnessed the increasing importance of the fly as a human disease model but studies on energy homeostasis and lipometabolism remain in their infancy. This perspective, addressing readers largely unfamiliar with the Drosophila model system, aims to highlight the starting points for which the fly could be employed to gain a deeper understanding of lipotoxicity and possibly contribute to strategies for the identification of novel drug targets relevant to type 2 diabetes mellitus and the metabolic syndrome.
Keywords: Drosophila; Lipotoxicity; Model organism; Energy homeostasis; Lipometabolism;

Lipotoxicity is the pathological consequence of lipid overflow in non-adipose tissue, mediated through reactive lipid moieties which may even lead to lipid-induced cell death (lipoapoptosis). This derailment of cellular and organismal fat homeostasis is the consequence of obesity due to continued over-feeding, and contributes substantially to the pathogenesis of insulin resistance, type 2 diabetes mellitus and cardiovascular disease, which are all components of the metabolic syndrome. Now, does yeast, a single-celled eukaryote, ever suffer from the metabolic syndrome and what can we potentially learn from studies in this organism about the underlying molecular mechanism that lead to lipid-associated pathologies in human cells? In this review I will summarize the remarkably conserved metabolic and regulatory processes relevant to establishing cellular energy and lipid homeostasis, as well as recent findings that provide detailed insights into the molecular mechanisms underlying fat-induced cellular malfunction and cell death, with potential implications also for mammalian cells.
Keywords: Saccharomyces cerevisiae; Schizosaccharomyces pombe; Unfolded protein response; TOR signaling; AMP-activated protein kinase; Apoptosis; Fatty acid toxicity; Lipolysis; Lipidomics;

Metabolomic strategies to study lipotoxicity in cardiovascular disease by Claire L. Waterman; Cheng Kian-Kai; Julian L. Griffin (230-234).
Cardiovascular disease arises from a combination of dyslipidaemia and systemic inflammation in both humans and mouse models of the disease. Given the strong metabolic component and also the strong interaction between diet and disease, one would expect strategies based on the global profiling of metabolism should hold substantial promise in defining the mechanism involved in this collection of pathologies. This review examines how metabolomics is being used both as a research tool to understand mechanisms of pathology and as an approach for biomarker discovery in cardiovascular disease. While the lipid fraction of blood plasma has a profound influence on the development of cardiovascular disease, there is also a growing body of evidence that the aqueous fraction of metabolites also have a role in following the effects of myocardial infarction and monitoring the development of atherosclerosis. Metabolomics has also been used in conjunction with proteomics and transcriptomics as part of a systems biology description of cardiovascular disease and in high-throughput approaches to profile large numbers of patients as part of epidemiology studies to understand how the genome interacts with the development of atherosclerosis.
Keywords: Atherosclerosis; ApoE; Metabonomic; Systems biology; Coronary artery disease; Myocardial infarction;

Systems biology views and studies the biological systems in the context of complex interactions between their building blocks and processes. Given its multi-level complexity, metabolic syndrome (MetS) makes a strong case for adopting the systems biology approach. Despite many MetS traits being highly heritable, it is becoming evident that the genetic contribution to these traits is mediated via gene–gene and gene–environment interactions across several spatial and temporal scales, and that some of these traits such as lipotoxicity may even be a product of long-term dynamic changes of the underlying genetic and molecular networks. This presents several conceptual as well as methodological challenges and may demand a paradigm shift in how we study the undeniably strong genetic component of complex diseases such as MetS. The argument is made here that for adopting systems biology approaches to MetS an integrative framework is needed which glues the biological processes of MetS with specific physiological mechanisms and principles and that lipotoxicity is one such framework. The metabolic phenotypes, molecular and genetic networks can be modeled within the context of such integrative framework and the underlying physiology.
Keywords: Allostasis; Gene network; Lipid metabolism; Lipidomics; Metabolomics; Systems biology;

The creative use of gnotobiotic animals, coupled with the development of modern metagenomic sequencing platforms and metabolomic profiling of biospecimens, has bestowed new insight into the remarkably intricate interface between the host mammal and its resident microbiota. As mutual benefactors, each partner exhibits evidence of adaptation: the host provides a hospitable habitat, giving consideration to its own species of origin, diet, genotype, geographical location, presence or absence of disease, and use of medications; the microbiota, in turn, configures its constituency, collective genome (microbiome), transcriptome, and metabolome to optimally suit its ecological niche. In this review, we discuss the mechanisms through which the gut microbiota and its host collaborate to regulate lipid metabolism, thereby influencing the metabolic response to nutrient intake and ultimately, the development of obesity and associated diseases such as lipotoxicity. These studies therefore demonstrate that the gut microbiota is an “environmental” influence whose synergistic interdependence with its host strongly suggests that we are in fact “supraorganisms.”
Keywords: Gut microbiota; Lipid metabolism; Obesity;

Acyl-CoA synthesis, lipid metabolism and lipotoxicity by Lei O. Li; Eric L. Klett; Rosalind A. Coleman (246-251).
Although the underlying causes of insulin resistance have not been completely delineated, in most analyses, a recurring theme is dysfunctional metabolism of fatty acids. Because the conversion of fatty acids to activated acyl-CoAs is the first and essential step in the metabolism of long-chain fatty acid metabolism, interest has grown in the synthesis of acyl-CoAs, their contribution to the formation of signaling molecules like ceramide and diacylglycerol, and their direct effects on cell function. In this review, we cover the evidence for the involvement of acyl-CoAs in what has been termed lipotoxicity, the regulation of the acyl-CoA synthetases, and the emerging functional roles of acyl-CoAs in the major tissues that contribute to insulin resistance and lipotoxicity, adipose, liver, heart and pancreas.
Keywords: Acyl-CoA; Triacylglycerol; ACSL; Diacylglycerol; Eicosanoid; Lipid channeling;

The accumulation of fat in tissues not suited for lipid storage has deleterious consequences on organ function, leading to cellular damage that underlies diabetes, heart disease, and hypertension. To combat these lipotoxic events, several therapeutics improve insulin sensitivity and/or ameliorate features of metabolic disease by limiting the inappropriate deposition of fat in peripheral tissues (i.e. thiazolidinediones, metformin, and statins). Recent advances in genomics and lipidomics have accelerated progress towards understanding the pathogenic events associated with the excessive production, underutilization, or inefficient storage of fat. Herein we review studies applying pharmacological or genetic strategies to manipulate the expression or activity of enzymes controlling lipid deposition, in order to gain a clearer understanding of the molecular mechanisms by which fatty acids contribute to metabolic disease.
Keywords: Lipotoxicity; Diabetes; Lipid; Sphingolipids; Insulin resistance; Genetic manipulation; Metabolism; Metabolic syndrome; Lipid metabolism;

Mitochondrial dysfunction and lipotoxicity by Patrick Schrauwen; Vera Schrauwen-Hinderling; Joris Hoeks; Matthijs K.C. Hesselink (266-271).
Mitochondrial dysfunction in skeletal muscle has been suggested to underlie the development of insulin resistance and type 2 diabetes mellitus. Reduced mitochondrial capacity will contribute to the accumulation of lipid intermediates, desensitizing insulin signaling and leading to insulin resistance. Why mitochondrial function is reduced in the (pre-)diabetic state is, however, so far unknown. Although it is tempting to suggest that skeletal muscle insulin resistance may result from an inherited or acquired reduction in mitochondrial function in the pre-diabetic state, it cannot be excluded that mitochondrial dysfunction may in fact be the consequence of the insulin-resistant/diabetic state. Lipotoxicity, the deleterious effects of accumulating fatty acids in skeletal muscle cells, may lie at the basis of mitochondrial dysfunction: next to producing energy, mitochondria are also the major source of reactive oxygen species (ROS). Fatty acids accumulating in the vicinity of mitochondria are vulnerable to ROS-induced lipid peroxidation. Subsequently, these lipid peroxides could have lipotoxic effects on mtDNA, RNA and proteins of the mitochondrial machinery, leading to mitochondrial dysfunction. Indeed, increased lipid peroxidation has been reported in insulin resistant skeletal muscle and the mitochondrial uncoupling protein-3, which has been suggested to prevent lipid-induced mitochondrial damage, is reduced in subjects with an impaired glucose tolerance and in type 2 diabetic patients. These findings support the hypothesis that fat accumulation in skeletal muscle may precede the reduction in mitochondrial function that is observed in type 2 diabetes mellitus.
Keywords: Lipotoxicity; Mitochondria; Type 2 diabetes; Muscle; Fatty acid;

Peroxisomes, lipid metabolism and lipotoxicity by R.J.A. Wanders; S. Ferdinandusse; P. Brites; S. Kemp (272-280).
Peroxisomes play an essential role in cellular lipid metabolism as exemplified by the existence of a number of genetic diseases in humans caused by the impaired function of one of the peroxisomal enzymes involved in lipid metabolism. Key pathways in which peroxisomes are involved include: (1.) fatty acid beta-oxidation; (2.) etherphospholipid biosynthesis, and (3.) fatty acid alpha-oxidation. In this paper we will describe these different pathways in some detail and will provide an overview of peroxisomal disorders of metabolism and in addition discuss the toxicity of the intermediates of peroxisomal metabolism as they accumulate in the different peroxisomal deficiencies.
Keywords: Fatty acid oxidation; Fatty acid; Plasmalogen; Bile acid; Zellweger syndrome; Adrenoleukodystrophy; Refsum disease;

The term lipotoxicity elicits visions of steatotic liver, fat laden skeletal muscles and engorged lipid droplets that spawn a number of potentially harmful intermediates that can wreak havoc on signal transduction and organ function. Prominent among these so-called lipotoxic mediators are signaling molecules such as long chain acyl-CoAs, ceramides and diacyglycerols; each of which is thought to engage serine kinases that disrupt the insulin signaling cascade, thereby causing insulin resistance. Defects in skeletal muscle fat oxidation have been implicated as a driving factor contributing to systemic lipid imbalance, whereas exercise-induced enhancement of oxidative potential is considered protective. The past decade of diabetes research has focused heavily on the foregoing scenario, and indeed the model is grounded in strong experimental evidence, albeit largely correlative. This review centers on mechanisms that connect lipid surplus to insulin resistance in skeletal muscle, as well as those that underlie the antilipotoxic actions of exercise. Emphasis is placed on recent studies that challenge accepted paradigms.
Keywords: Skeletal muscle; Lipid; Fat oxidation; Mitochondria; Exercise; Obesity; Diabetes; Insulin action;

Glucolipotoxicity of the pancreatic beta cell by Vincent Poitout; Julie Amyot; Meriem Semache; Bader Zarrouki; Derek Hagman; Ghislaine Fontés (289-298).
The concept of glucolipotoxicity refers to the combined, deleterious effects of elevated glucose and fatty acid levels on pancreatic beta-cell function and survival. Significant progress has been made in recent years towards a better understanding of the cellular and molecular basis of glucolipotoxicity in the beta cell. The permissive effect of elevated glucose on the detrimental actions of fatty acids stems from the influence of glucose on intracellular fatty acid metabolism, promoting the synthesis of cellular lipids. The combination of excessive levels of fatty acids and glucose therefore leads to decreased insulin secretion, impaired insulin gene expression, and beta-cell death by apoptosis, all of which probably have distinct underlying mechanisms. Recent studies from our laboratory have identified several pathways implicated in fatty acid inhibition of insulin gene expression, including the extracellular-regulated kinase (ERK1/2) pathway, the metabolic sensor Per-Arnt-Sim kinase (PASK), and the ATF6 branch of the unfolded protein response. We have also confirmed in vivo in rats that the decrease in insulin gene expression is an early defect which precedes any detectable abnormality in insulin secretion. While the role of glucolipotoxicity in humans is still debated, the inhibitory effects of chronically elevated fatty acid levels has been clearly demonstrated in several studies, at least in individuals genetically predisposed to developing type 2 diabetes. It is therefore likely that glucolipotoxicity contributes to beta-cell failure in type 2 diabetes as well as to the decline in beta-cell function observed after the onset of the disease.
Keywords: Fatty acid; Glucose; Islet of Langerhans; Diabetes; Insulin;

Fatty liver and lipotoxicity by Michael Trauner; Marco Arrese; Martin Wagner (299-310).
Fatty liver disease comprises a spectrum ranging from simple steatosis to steatohepatitis which can progress to liver cirrhosis and hepatocellular cancer. Hepatic lipotoxicity may ensue when the hepatic capacity to utilize, store and export fatty acids (FA) as triglycerides is overwhelmed. Additional mechanisms of hepatic lipotoxicity include abnormal FA oxidation with formation of reactive oxygen species, disturbances in cellular membrane FA and phospholipid composition, alterations of cholesterol content and ceramide signalling. Lipotoxicity is a key factor for the progression of fatty liver disease by inducing hepatocellular death, activating Kupffer cells and an inflammatory response, impairing hepatic insulin signalling resulting in insulin resistance, and activation of a fibrogenic response in hepatic stellate cells that can ultimately lead to cirrhosis. Therefore, the concept of hepatic lipotoxicity should be considered in future therapeutic concepts for fatty liver disease.
Keywords: Non-alcoholic fatty liver disease; Steatohepatitis; Lipotoxicity; Fatty acid;

Lipotoxicity in the heart by Adam R. Wende; E. Dale Abel (311-319).
Obesity and insulin resistance are associated with ectopic lipid deposition in multiple tissues, including the heart. Excess lipid may be stored as triglycerides, but are also shunted into non-oxidative pathways that disrupt normal cellular signaling leading to organ dysfunction and in some cases apoptosis, a process termed lipotoxicity. Various pathophysiological mechanisms have been proposed to lead to lipotoxic tissue injury, which might vary by cell type. Specific mechanisms by which lipotoxicity alter cardiac structure and function are incompletely understood, but are beginning to be elucidated. This review will focus on mechanisms that have been proposed to lead to lipotoxic injury in the heart and will review the state of knowledge regarding potential causes and correlates of increased myocardial lipid content in animal models and humans. We will seek to highlight those areas where additional research is warranted.
Keywords: Heart; Diabetes; Obesity; Lipotoxicity;

Insulin resistance, lipotoxicity and endothelial dysfunction by Helen Imrie; Afroze Abbas; Mark Kearney (320-326).
The number of people with the insulin-resistant conditions of type 2 diabetes mellitus (T2DM) and obesity has reached epidemic proportions worldwide. Eighty percent of people with T2DM will die from the complications of cardiovascular atherosclerosis. Insulin resistance is characterised by endothelial dysfunction, which is a pivotal step in the initiation/progression of atherosclerosis. A hallmark of endothelial dysfunction is an unfavourable imbalance between the bioavailability of the antiatherosclerotic signalling molecule nitric oxide (NO) and proatherosclerotic reactive oxygen species. In this review we discuss the mechanisms linking insulin resistance to endothelial dysfunction, with a particular emphasis on a potential role for a toxic effect of free fatty acids on endothelial cell homeostasis.
Keywords: Nitric oxide; Reactive oxygen species; Free fatty acid;

Lipotoxicity in macrophages: evidence from diseases associated with the metabolic syndrome by Xavier Prieur; Tamás Rőszer; Mercedes Ricote (327-337).
Accumulation of lipid metabolites within non-adipose tissues can induce chronic inflammation by promoting macrophage infiltration and activation. Oxidized and glycated lipoproteins, free fatty acids, free cholesterol, triacylglycerols, diacylglycerols and ceramides have long been known to induce cellular dysfunction through their pro-inflammatory and pro-apoptotic properties. Emerging evidence suggests that macrophage activation by lipid metabolites and further modulation by lipid signaling represents a common pathogenic mechanism underlying lipotoxicity in atherosclerosis, obesity-associated insulin resistance and inflammatory diseases related to metabolic syndrome such as liver steatosis and chronic kidney disease. In this review, we discuss the latest discoveries that support the role of lipids in modulating the macrophage phenotype in different metabolic diseases. We describe the common mechanisms by which lipid derivatives, through modulation of macrophage function, promote plaque instability in the arterial wall, impair insulin responsiveness and contribute to inflammatory liver, muscle and kidney disease. We discuss the molecular mechanism of lipid activation of pro-inflammatory pathways (JNK, NFκB) and the key roles played by the PPAR and LXR nuclear receptors—lipid sensors that link lipid metabolism and inflammation.
Keywords: Lipotoxicity; Macrophage; Nuclear receptor; Inflammation; Insulin resistance; Atherosclerosis;

While the link between obesity and type 2 diabetes is clear on an epidemiological level, the underlying mechanism linking these two common disorders is not as clearly understood. One hypothesis linking obesity to type 2 diabetes is the adipose tissue expandability hypothesis. The adipose tissue expandability hypothesis states that a failure in the capacity for adipose tissue expansion, rather than obesity per se is the key factor linking positive energy balance and type 2 diabetes. All individuals possess a maximum capacity for adipose expansion which is determined by both genetic and environmental factors. Once the adipose tissue expansion limit is reached, adipose tissue ceases to store energy efficiently and lipids begin to accumulate in other tissues. Ectopic lipid accumulation in non-adipocyte cells causes lipotoxic insults including insulin resistance, apoptosis and inflammation. This article discusses the links between adipokines, inflammation, adipose tissue expandability and lipotoxicity. Finally, we will discuss how considering the concept of allostasis may enable a better understanding of how diabetes develops and allow the rational design of new anti diabetic treatments.
Keywords: Adipose; Expandabillity; Lipotoxicity; Allostasis; Insulin resistance; Type 2 diabetes;

Hypothalamic lipotoxicity and the metabolic syndrome by Pablo B. Martínez de Morentin; Luis Varela; Johan Fernø; Rubén Nogueiras; Carlos Diéguez; Miguel López (350-361).
Ectopic accumulation of lipids in peripheral tissues, such as pancreatic β cells, liver, heart and skeletal muscle, leads to lipotoxicity, a process that contributes substantially to the pathophysiology of insulin resistance, type 2 diabetes, steatotic liver disease and heart failure. Current evidence has demonstrated that hypothalamic sensing of circulating lipids and modulation of hypothalamic endogenous fatty acid and lipid metabolism are two bona fide mechanisms modulating energy homeostasis at the whole body level. Key enzymes, such as AMP-activated protein kinase (AMPK) and fatty acid synthase (FAS), as well as intermediate metabolites, such as malonyl-CoA and long-chain fatty acids-CoA (LCFAs-CoA), play a major role in this neuronal network, integrating peripheral signals with classical neuropeptide-based mechanisms. However, one key question to be addressed is whether impairment of lipid metabolism and accumulation of specific lipid species in the hypothalamus, leading to lipotoxicity, have deleterious effects on hypothalamic neurons. In this review, we summarize what is known about hypothalamic lipid metabolism with focus on the events associated to lipotoxicity, such as endoplasmic reticulum (ER) stress in the hypothalamus. A better understanding of these molecular mechanisms will help to identify new drug targets for the treatment of obesity and metabolic syndrome.
Keywords: Endoplasmic reticulum (ER) stress; Fatty acids; Hypothalamus; Lipid metabolism; Lipid sensing; Lipotoxicity;

n-3 PUFA and lipotoxicity by Pablo Perez-Martinez; Francisco Perez-Jimenez; Jose Lopez-Miranda (362-366).
Excess lipid accumulation in nonadipose tissues may occur in the setting of high levels of plasma free fatty acids or triglycerides (TGs) in a process called “lipotoxicity”. Evidence from human studies and animal models suggests that lipid accumulation in the heart, skeletal muscle, pancreas, and liver play an important role in the pathogenesis of heart failure, obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). During the past few years, several studies have shown that n-3 polyunsaturated fatty acids (PUFA) have potentially cardioprotective effects, especially in high-risk patients with dyslipidemia, and might therefore be expected to be of benefit in T2DM. Moreover, new information has demonstrated the beneficial effects of consuming n-3 PUFA in preventing the complications of lipotoxicity. n-3 PUFA dietary intake thus had positive effects on fatty liver in patients with non-alcoholic fatty liver disease (NAFLD), with an improvement in liver echotexture and a significant regression of hepatic brightness, associated with improved liver hemodynamics. The n-3 PUFA also had beneficial effects on ectopic fat accumulation inside the heart, with stabilization of cardiac myocytes and antiarrhythmic effects. On the other hand, recent data from animal models suggest that oral dosing of eicosapentaenoic acid (EPA) could contribute to protect against β-cell lipotoxicity. This review discusses the latest hypotheses regarding lipotoxicity, concentrating on the impact of the n-3 PUFA that contribute to ectopic lipid storage, affecting organ function. Further human studies are needed to test the evidence and elucidate the mechanisms involved in this process.
Keywords: n-3 PUFA; Lipotoxicity; Triglycerides; Metabolic syndrome; Lipid accumulation; Lipoapoptosis;

The role of dietary protein on lipotoxicity by Armando R. Tovar; Nimbe Torres (367-371).
Lipotoxicity is a metabolic abnormality frequently observed during the development of obesity and is the main cause of several changes in the metabolic observed during metabolic syndrome. Consistent consumption of diets high in saturated fat or simple carbohydrates combined with low physical activity are the main causes of obesity and its comorbidities. However, the contribution of dietary protein and, in particular, the contribution due to the type of dietary protein, to the process of obesity and its metabolic consequences are less well-understood. In this review, we showed that the type of dietary protein has a significant contribution to the process of lipotoxicity through the modulation of insulin secretion and the regulation of adipocyte metabolic function. Consumption of soy protein stimulates insulin secretion to a lower extent than casein despite the fact that both are high-quality proteins. The amino acid profiles of soy protein and its isoflavones are responsible for the reduced insulin secretion. Also, soy protein increases insulin sensitivity, whereas casein has the opposite effect. Consequently, soy protein reduces SREBP-1 expression in the liver leading to low accumulation of hepatic triglycerides, despite the consumption of a high-fat diet. Furthermore, soy protein reduces adipocyte hypertrophy, hyperleptinemia, and free fatty acid concentration. Thus, the influx of FA into the liver decreases, and hepatic oxidation of FA increases. These metabolic changes result in a decrease in lipid depots and ceramide which reduce hepatic lipotoxicity, whereas casein produces the opposite effect. This study emphasizes that the type of dietary protein has an important effect on lipotoxicity.
Keywords: Dietary protein; Lipogenesis; Obesity; Adipocyte; Insulin secretion; Lipotoxicity;

The role of white and brown adipose tissues in energy metabolism is well established. However, the existence of brown fat in adult humans was until very recently a matter of debate, and the molecular mechanisms underlying brown adipocyte development remained largely unknown. In 2009, several studies brought direct evidence for functional brown adipose tissue in adults. New factors involved in brown fat cell differentiation have been identified. Moreover, work on the origin of fat cells took an unexpected path with the recognition of different populations of brown fat cell precursors according to the anatomical location of the fat depots: a precursor common to skeletal muscle cells and brown adipocytes from brown fat depots, and a progenitor cell common to white adipocytes and brown adipocytes that appear in certain conditions in white fat depots. There is also mounting evidence that mature white adipocytes, including human fat cells, can be converted into brown fat-like adipocytes, and that the typical fatty acid storage phenotype of white adipocyte can be altered towards a fat utilization phenotype. These data open up new opportunities for the development of drugs for obesity and its metabolic and cardiovascular complications.
Keywords: Adipose tissue; Brown adipocyte; White fat cell; Fatty acid; Obesity;

Ectopic lipid accumulation is promoted by obesity and an impaired ability to accumulate triglycerides in the subcutaneous depots. The adipose tissue is dysregulated in hypertrophic obesity, i.e., when the adipose cells have become enlarged. In some individuals, however, obesity is a consequence of a recruitment of new adipocytes, i.e., a hyperplastic obesity. This form of obesity is usually not associated with the metabolic complications and is termed “obese but metabolically normal”. We here review recent findings showing that hypertrophic obesity is associated with an impaired differentiation of committed preadipocytes. This may be a primary (genetic?) event, thus leading to hypertrophic fat cells and the associated inflammation. However, it is also possible that the inflammation is a primary event allowing, in particular, TNFα to inhibit preadipocyte differentiation. TNFα, instead, promotes a partial transdifferentiation of the preadipocytes to assume a macrophage-like phenotype. PPARγ activation promotes adipogenesis but can apparently not overcome the impaired preadipocyte differentiation seen in hypertrophic obesity.
Keywords: Adipose tissue; Obesity; PPARγ; Adipogenesis; TNFα;

Evolving evidence suggest that metabolic requirements for cell proliferation are identical in all normal and cancer cells. HER2 oncogene-overexpressors, a highly aggressive subtype of human cancer cells, constitute one of the best examples of how malignant cells maximize their ability to acquire and metabolize nutrients in a manner conductive to proliferation rather than efficient ATP production. HER2-overexpressors optimize their requirements of rapid cancer cell growth by fine-tuning a double [lipogenic/lipolytic]-edged metabolic sword. On the one edge, HER2 oncogene overexpression triggers redundant signaling cascades to ensure that all the major enzymes involved in de novo fatty acid (FA) synthesis will facilitate aerobic glycolysis instead of oxidative phosphorylation for energy production (Warburg effect). HER2 also establishes a positive bidirectional relationship with the key lipogenic enzyme Fatty Acid Synthase (FASN) that rapidly senses and respond to any disturbance in the flux of lipogenic substrates (e.g. NADPH and acetyl-CoA) and lipogenesis end-products (i.e. palmitate). On the other edge, HER2 overexpression arranges detoxifying mechanisms by upregulating PPARγ, a well established positive regulator role of adipogenesis and lipid storage in cell types with active lipid metabolism. PPARγ establishes a lipogenesis/lipolysis joining-point that enables HER2-positive cancer cells to avoid endogenous palmitate toxicity while securing palmitate into fat stores to avoid palmitate feedback on FASN functioning. The ability of HER2 to supercharge lipogenesis (by activating regulatory circuits that activate and fuel the lipogenic enzyme FASN) while averting lipotoxicity (by promoting conversion and storage of excess FAs to triglycerides in a PPARγ-dependent manner) supports the notion that best adapted cancer phenotypes are addicted to oncogenic lipid metabolism for cell proliferation and survival. It is conceptually attractive to assume that we can crash HER2-driven rapid cell proliferation by inhibiting “motor refueling” (upon blockade of lipogenic enzymes), by losing the “lipolytic brake” (upon blockade of PPARγ) and/or by sticking the “lipogenic gas pedal” (upon supplementation with dietary FAs).
Keywords: HER2; Fatty Acid Synthase; PPARγ; Lipogenesis; Lipolysis; Cancer;

A subset of HIV-1-infected patients undergoing antiretroviral treatment develops a lipodystrophy syndrome. It is characterized by loss of peripheral subcutaneous adipose tissue (face, limbs, buttocks), visceral fat accumulation, and, in some cases, lipomatosis, especially in the dorsocervical area. In addition, these patients show metabolic alterations reminiscent of the metabolic syndrome, particularly dyslipidemia and insulin resistance. These alterations lead to enhanced cardiovascular risk in patients and favor the development of diabetes. Although a complex combination of HIV-1 infection and drug treatment-related events triggers the syndrome, lipotoxicity appears to contribute to the development of the syndrome. Active lipolysis in subcutaneous fat, combined with impaired fat storage capacity in the subcutaneous depot, drive ectopic deposition of lipids, either in the visceral depot or in nonadipose sites. Both hepatic steatosis and increased lipid content in skeletal muscle take place and surely contribute to systemic metabolic alterations, especially insulin resistance. Pancreatic function may also be affected by the exposure to high levels of fatty acids; together with direct effects of antiretroviral drugs, this may contribute to impaired insulin release and a prodiabetic state in the patients. Addressing lipotoxicity as a pathogenic actor in the lipodystrophy syndrome should be considered in strategies for treating and/or preventing the morphological alterations and systemic metabolic disturbances associated with lipodystrophy.
Keywords: Lipodystrophy; HIV; Mitochondria; Brown adipose tissue; Inflammation;

The risk functions for obesity (defined as the quantitative relation between degree of obesity throughout its range and the risk of health problems) have been used to define ‘obesity’ as an excess storage of fat in the body to such an extent that it causes health problems leading to increased mortality. The lipotoxicity theory implies that the fat stored in droplets of triglycerides in the cells are biologically inert and that the metabolic dysfunctions are primarily due to the increased exposure of the cells to fatty acids. If this is true, it has profound implications for the interpretations of the multiple epidemiological studies of the risk functions. It is obvious from all these studies that the sizes of the fat depots are risk indicators of health effects in various ways. Paradoxically, the sizes of the fat stores are also indicators of the preceding implementation of the ability of the body to protect itself against the toxic effects of the free fatty acids. The current risk of metabolic dysfunctions appears to be determined by the balance between the rate of loading of the body with fatty acids and the rate of eliminating the fatty acids by either triglyceride storage or oxidation. The progress in the development of the dysfunction then depends on the persistence of the imbalance leading to future cumulative exposure of the cells to the toxic effects of the fatty acids rather than on the current size of the fat depots. This may be considered as a reason for changing the definition of obesity to one based on better estimates of future risks of health problems derived from later metabolic dysfunctions rather than on the past coping with the exposure to the fatty acids by storage as triglycerides. Implementation of such definition would require a test that measures this residual capacity to avoid excess exposure of the cells to the fatty acids before the metabolic dysfunctions have emerged. In analogy with the glucose tolerance test, a fatty acid tolerance test may be needed to identify individuals who are at a level of risk for developing lipotoxicity induced metabolic dysfunctions such that they require intervention. This test would ideally be a single biomarker that would determine residual capacity for adipose expansion, fatty acid oxidation and safe ectopic lipid deposition.
Keywords: Adipose tissue; Expandability; Lipotoxicity; Obesity; Insulin resistance; Metabolic syndrome; Type 2 diabetes;