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Futile lipid cycling: from biochemistry to physiology.
Sharma, AK, Khandelwal, R, Wolfrum, C
Nature metabolism. 2024
Abstract
In the healthy state, the fat stored in our body isn't just inert. Rather, it is dynamically mobilized to maintain an adequate concentration of fatty acids (FAs) in our bloodstream. Our body tends to produce excess FAs to ensure that the FA availability is not limiting. The surplus FAs are actively re-esterified into glycerides, initiating a cycle of breakdown and resynthesis of glycerides. This cycle consumes energy without generating a new product and is commonly referred to as the 'futile lipid cycle' or the glyceride/FA cycle. Contrary to the notion that it's a wasteful process, it turns out this cycle is crucial for systemic metabolic homeostasis. It acts as a control point in intra-adipocyte and inter-organ cross-talk, a metabolic rheostat, an energy sensor and a lipid diversifying mechanism. In this Review, we discuss the metabolic regulation and physiological implications of the glyceride/FA cycle and its mechanistic underpinnings.
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Futile cycles: Emerging utility from apparent futility.
Sharma, AK, Khandelwal, R, Wolfrum, C
Cell metabolism. 2024
Abstract
Futile cycles are biological phenomena where two opposing biochemical reactions run simultaneously, resulting in a net energy loss without appreciable productivity. Such a state was presumed to be a biological aberration and thus deemed an energy-wasting "futile" cycle. However, multiple pieces of evidence suggest that biological utilities emerge from futile cycles. A few established functions of futile cycles are to control metabolic sensitivity, modulate energy homeostasis, and drive adaptive thermogenesis. Yet, the physiological regulation, implication, and pathological relevance of most futile cycles remain poorly studied. In this review, we highlight the abundance and versatility of futile cycles and propose a classification scheme. We further discuss the energetic implications of various futile cycles and their impact on basal metabolic rate, their bona fide and tentative pathophysiological implications, and putative drug interactions.
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Mechanisms and clinical relevance of the bidirectional relationship of viral infections with metabolic diseases.
Perakakis, N, Harb, H, Hale, BG, Varga, Z, Steenblock, C, Kanczkowski, W, Alexaki, VI, Ludwig, B, Mirtschink, P, Solimena, M, et al
The lancet. Diabetes & endocrinology. 2023;(9):675-693
Abstract
Viruses have been present during all evolutionary steps on earth and have had a major effect on human history. Viral infections are still among the leading causes of death. Another public health concern is the increase of non-communicable metabolic diseases in the last four decades. In this Review, we revisit the scientific evidence supporting the presence of a strong bidirectional feedback loop between several viral infections and metabolic diseases. We discuss how viruses might lead to the development or progression of metabolic diseases and conversely, how metabolic diseases might increase the severity of a viral infection. Furthermore, we discuss the clinical relevance of the current evidence on the relationship between viral infections and metabolic disease and the present and future challenges that should be addressed by the scientific community and health authorities.
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Master of disguise: deconvoluting adipose tissue heterogeneity and its impact on metabolic health.
Dewal, RS, Wolfrum, C
Current opinion in genetics & development. 2023;:102085
Abstract
Adipose tissue in its different forms: white, brown, and beige, while essential in day-to-day bodily functions, leads to several disorders when present in overabundance, including obesity and type-2 diabetes. Adipose tissue function/dysfunction is largely mediated by the diversity of its cell composition, within adipocytes and cells in its stromal fraction. Owing to its heterogeneous nature, recent studies have focused on intercalating the effects of cellular diversity with adipose tissue function, particularly by employing sequencing technologies. In this review, we highlight the recent advances in utilizing single-cell and single-nuclei RNA sequencing technologies to discover novel adipose tissue cell types or subtypes, and to determine their role in mediating tissue, as well as whole-body metabolism and function.
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Cross-Talk of NADPH Oxidases and Inflammation in Obesity.
Morawietz, H, Brendel, H, Diaba-Nuhoho, P, Catar, R, Perakakis, N, Wolfrum, C, Bornstein, SR
Antioxidants (Basel, Switzerland). 2023;(8)
Abstract
Obesity is a major risk factor for cardiovascular and metabolic diseases. Multiple experimental and clinical studies have shown increased oxidative stress and inflammation linked to obesity. NADPH oxidases are major sources of reactive oxygen species in the cardiovascular system and in metabolically active cells and organs. An impaired balance due to the increased formation of reactive oxygen species and a reduced antioxidative capacity contributes to the pathophysiology of cardiovascular and metabolic diseases and is linked to inflammation as a major pathomechanism in cardiometabolic diseases. Non-alcoholic fatty liver disease is particularly characterized by increased oxidative stress and inflammation. In recent years, COVID-19 infections have also increased oxidative stress and inflammation in infected cells and tissues. Increasing evidence supports the idea of an increased risk for severe clinical complications of cardiometabolic diseases after COVID-19. In this review, we discuss the role of oxidative stress and inflammation in experimental models and clinical studies of obesity, cardiovascular diseases, COVID-19 infections and potential therapeutic strategies.
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Sexual dimorphism in COVID-19: potential clinical and public health implications.
Bechmann, N, Barthel, A, Schedl, A, Herzig, S, Varga, Z, Gebhard, C, Mayr, M, Hantel, C, Beuschlein, F, Wolfrum, C, et al
The lancet. Diabetes & endocrinology. 2022;(3):221-230
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Abstract
Current evidence suggests that severity and mortality of COVID-19 is higher in men than in women, whereas women might be at increased risk of COVID-19 reinfection and development of long COVID. Differences between sexes have been observed in other infectious diseases and in the response to vaccines. Sex-specific expression patterns of proteins mediating virus binding and entry, and divergent reactions of the immune and endocrine system, in particular the hypothalamic-pituitary-adrenal axis, in response to acute stress might explain the higher severity of COVID-19 in men. In this Personal View, we discuss how sex hormones, comorbidities, and the sex chromosome complement influence these mechanisms in the context of COVID-19. Due to its role in the severity and progression of SARS-CoV-2 infections, we argue that sexual dimorphism has potential implications for disease treatment, public health measures, and follow-up of patients predisposed to the development of long COVID. We suggest that sex differences could be considered in future pandemic surveillance and treatment of patients with COVID-19 to help to achieve better disease stratification and improved outcomes.
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7.
Novel insights into adipose tissue heterogeneity.
Wang, T, Sharma, AK, Wolfrum, C
Reviews in endocrine & metabolic disorders. 2022;(1):5-12
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Abstract
When normalized to volume, adipose tissue is comprised mainly of large lipid metabolizing and storing cells called adipocytes. Strikingly, the numerical representation of non-adipocytes, composed of a wide variety of cell types found in the so-called stromal vascular fraction (SVF), outnumber adipocytes by far. Besides its function in energy storage, adipose tissue has emerged as a versatile organ that regulates systemic metabolism and has therefore constituted an attractive target for the treatment of metabolic diseases. Recent high-resolution single cells/nucleus RNA seq data exemplify an intriguingly profound diversity of both adipocytes and SVF cells in all adipose depots, and the current data, while limited, demonstrate the significance of the intra-tissue cell composition in shaping the overall functionality of this tissue. Due to the complexity of adipose tissue, our understanding of the biological relevance of this heterogeneity and plasticity is fractional. Therefore, establishing atlases of adipose tissue cell heterogeneity is the first step towards generating an understanding of these functionalities. In this review, we will describe the current knowledge on adipose tissue cell composition and the heterogeneity of single-cell RNA sequencing, including the technical limitations.
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Plasticity and heterogeneity of thermogenic adipose tissue.
Sun, W, Modica, S, Dong, H, Wolfrum, C
Nature metabolism. 2021;(6):751-761
Abstract
The perception of adipose tissue, both in the scientific community and in the general population, has changed dramatically in the past 20 years. While adipose tissue was thought for a long time to be a rather simple lipid storage entity, it is now recognized as a highly heterogeneous organ and a critical regulator of systemic metabolism, composed of many different subtypes of cells, with important endocrine functions. Additionally, adipose tissue is nowadays recognized to contribute to energy turnover, due to the presence of specialized thermogenic adipocytes, which can be found in many adipose depots. This review discusses the unprecedented insights that we have gained into the heterogeneity of thermogenic adipocytes and their respective precursors due to the technical developments in single-cell and nucleus technologies. These methodological advances have increased our understanding of how adipose tissue catabolic function is influenced by developmental and intercellular communication events.
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Brown Adipose Crosstalk in Tissue Plasticity and Human Metabolism.
Scheele, C, Wolfrum, C
Endocrine reviews. 2020;41(1)
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Plain language summary
Brown adipose tissue (BAT) is an important contributor to the regulation of metabolism via cellular communication with organs such as liver, muscle, gut and central nervous system. BAT is important for heat generation and is at high levels in human infants. Levels of activation of BAT decline as we age and it has been shown that the amount of BAT is smaller and its activity reduced in those with obesity and type 2 diabetes. To date, there is no answer to efficiently restore functional BAT in aging and obese subjects. This review looks at experiments done on the factors secreted from active BAT (batokines). The review aims to provide a structure for the processes and cell types involved in BAT and the recent findings of BAT whole-body communication are discussed. Altogether, these findings demonstrate that BAT has an adaptive capacity. Studying batokines, offers an alternative approach to identify novel drug targets for metabolic regulation.
Abstract
Infants rely on brown adipose tissue (BAT) as a primary source of thermogenesis. In some adult humans, residuals of brown adipose tissue are adjacent to the central nervous system and acute activation increases metabolic rate. Brown adipose tissue (BAT) recruitment occurs during cold acclimation and includes secretion of factors, known as batokines, which target several different cell types within BAT, and promote adipogenesis, angiogenesis, immune cell interactions, and neurite outgrowth. All these processes seem to act in concert to promote an adapted BAT. Recent studies have also provided exciting data on whole body metabolic regulation with a broad spectrum of mechanisms involving BAT crosstalk with liver, skeletal muscle, and gut as well as the central nervous system. These widespread interactions might reflect the property of BAT of switching between an active thermogenic state where energy is highly consumed and drained from the circulation, and the passive thermoneutral state, where energy consumption is turned off. (Endocrine Reviews 41: XXX - XXX, 2020).
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Hemostasis, endothelial stress, inflammation, and the metabolic syndrome.
Grandl, G, Wolfrum, C
Seminars in immunopathology. 2018;40(2):215-224
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Plain language summary
The metabolic syndrome consists of several factors that significantly increase the risk of developing type 2 diabetes, cardiovascular disease and all-cause mortality. Underlying these conditions is a complex interaction between the immune response, blood glucose levels, blood lipid levels and both local and systemic inflammation. The purpose of this review is to provide an overview of various aspects of pathophysiology in metabolic syndrome and obesity through the lens of the western diet. According to the existing research, the authors conclude that both type 2 diabetes and cardiovascular disease should be viewed as an inflammatory disease and further suggest inflammation and insulin resistance are linked to chronic consumption of a western diet.
Abstract
Obesity and the metabolic syndrome (MS) are two of the pressing healthcare problems of our time. The MS is defined as increased abdominal obesity in concert with elevated fasting glucose levels, insulin resistance, elevated blood pressure, and plasma lipids. It is a key risk factor for type 2 diabetes mellitus (T2DM) and for cardiovascular complications and mortality. Here, we review work demonstrating that various aspects of coagulation and hemostasis, as well as vascular reactivity and function, become impaired progressively during chronic ingestion of a western diet, but also acutely after meals. We outline that both T2DM and cardiovascular disease should be viewed as inflammatory diseases and describe that chronic overload of free fatty acids and glucose can trigger inflammatory pathways directly or via increased production of ROS. We propose that since endothelial stress and increases in platelet activity precede inflammation and overt symptoms of the MS, they are likely the first hit. This suggests that endothelial activation and insulin resistance are probably causative in the observed chronic low-level metabolic inflammation, and thus both metabolic and cardiovascular complications linked to consumption of a western diet.