Christine M. Kusminski

Diabetes and apoptosis: lipotoxicity

Obesity is an established risk factor in the pathogenesis of insulin resistance, type 2 diabetes mellitus and cardiovascular disease; all components that are part of the metabolic syndrome. Traditionally, insulin resistance has been defined in a glucocentric perspective. However, elevated systemic levels of fatty acids are now considered significant contributors towards the pathophysiological aspects associated with the syndrome. An overaccumulation of unoxidized long-chain fatty acids can saturate the storage capacity of adipose tissue, resulting in a lipid ‘spill over’ to non-adipose tissues, such as the liver, muscle, heart, and pancreatic-islets. Under these circumstances, such ectopic lipid deposition can have deleterious effects. The excess lipids are driven into alternative non-oxidative pathways, which result in the formation of reactive lipid moieties that promote metabolically relevant cellular dysfunction (lipotoxicity) and programmed cell-death (lipoapoptosis). Here, we focus on how both of these processes affect metabolically significant cell-types and highlight how lipotoxicity and sequential lipoapoptosis are as major mediators of insulin resistance, diabetes and cardiovascular disease.

MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity

We examined mouse models with altered adipocyte expression of mitoNEET, a protein residing in the mitochondrial outer membrane, to probe its impact on mitochondrial function and subsequent cellular responses. We found that overexpression of mitoNEET enhances lipid uptake and storage, leading to an expansion of the mass of adipose tissue. Despite the resulting massive obesity, benign aspects of adipose tissue expansion prevail, and insulin sensitivity is preserved. Mechanistically, we also found that mitoNEET inhibits mitochondrial iron transport into the matrix and, because iron is a rate-limiting component for electron transport, lowers the rate of β-oxidation. This effect is associated with a lower mitochondrial membrane potential and lower levels of reactive oxygen species–induced damage, along with increased production of adiponectin. Conversely, a reduction in mitoNEET expression enhances mitochondrial respiratory capacity through enhanced iron content in the matrix, ultimately corresponding to less weight gain on a high-fat diet. However, this reduction in mitoNEET expression also causes heightened oxidative stress and glucose intolerance. Thus, manipulation of mitochondrial function by varying mitoNEET expression markedly affects the dynamics of cellular and whole-body lipid homeostasis.

Mitochondrial dysfunction in white adipose tissue

Although mitochondria in brown adipose tissue and their role in non-shivering thermogenesis have been widely studied, we have only a limited understanding of the relevance of mitochondria in white adipose tissue (WAT) for cellular homeostasis of the adipocyte and their impact upon systemic energy homeostasis. A better understanding of the regulatory role that white adipocyte mitochondria play in the regulation of whole-body physiology becomes increasingly important. WAT mitochondrial biogenesis can effectively be induced pharmacologically using a number of agents, including PPARγ agonists. Through their ability to influence key biochemical processes central to the adipocyte, such as fatty acid (FA) esterification and lipogenesis, as well as their impact upon the production and release of key adipokines, mitochondria play a crucial role in determining systemic insulin sensitivity.

Targeting adipose tissue in the treatment of obesity-associated diabetes

Adipose tissue regulates numerous physiological processes, and its dysfunction in obese humans is associated with disrupted metabolic homeostasis, insulin resistance and type 2 diabetes mellitus (T2DM). Although several US-approved treatments for obesity and T2DM exist, these are limited by adverse effects and a lack of effective long-term glucose control. In this Review, we provide an overview of the role of adipose tissue in metabolic homeostasis and assess emerging novel therapeutic strategies targeting adipose tissue, including adipokine-based strategies, promotion of white adipose tissue beiging as well as reduction of inflammation and fibrosis.

The Road From Discovery to Clinic: Adiponectin as a Biomarker of Metabolic Status

Biomarkers are globally used to monitor clinical responses to therapeutic and lifestyle interventions. The adipocyte‐derived hormone adiponectin is recognized as a promising new biomarker owing to its many associations with components of the metabolic syndrome. The study described by Wagner and colleagues in this issue offers a first example of how a large‐scale effort in the context of a cross‐company collaborative study in the pharmaceutical industry can offer a powerful tool for the further validation of a new biomarker in the context of pharmacological intervention with peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) agonists. 1

MitoNEET-mediated effects on browning of white adipose tissue

MitoNEET is an outer mitochondrial membrane protein that, upon overexpression in white adipose tissue (WAT), exerts a positive impact on tissue expansion and whole-body lipid and carbohydrate homeostasis by altering mitochondrial matrix iron metabolism. Here we determine the key transcriptional events in subcutaneous WAT of mice in response to mitoNEET overexpression and a high-fat diet (HFD). Microarray analyses at key points during weight gain upon body-weight divergence with wild-type mice demonstrate that mitoNEET-enriched sWAT early on upregulates a browning signature program that limits WAT expansion in transgenic mice for a period of up to 12-weeks of HFD. This compensatory browning phenotype is subsequently lost, resulting in rapid WAT expansion and body-weight gain. Exposure to thermoneutral temperatures during HFD prompts weight gain significantly earlier. Similar WAT expansion is achieved upon infection with an adeno-associated virus expressing mitoNEET. Collectively, the mitoNEET enriched fat-pads feature a more vascularized, anti-inflammatory and less fibrotic environment.

E4orf1 induction in adipose tissue promotes insulin-independent signaling in the adipocyte

Background/Purpose Type 2 diabetes remains a worldwide epidemic with major pathophysiological changes as a result of chronic insulin resistance. Insulin regulates numerous biochemical pathways related to carbohydrate and lipid metabolism. Methods We have generated a novel mouse model that allows us to constitutively activate, in an inducible fashion, the distal branch of the insulin signaling transduction pathway specifically in adipocytes. Results Using the adenoviral 36 E4orf1 protein, we chronically stimulate locally the Ras-ERK-MAPK signaling pathway. At the whole body level, this leads to reduced body-weight gain under a high fat diet challenge. Despite overlapping glucose tolerance curves, there is a reduced requirement for insulin action under these conditions. The mice further exhibit reduced circulating adiponectin levels that ultimately lead to impaired lipid clearance, and inflamed and fibrotic white adipose tissues. Nevertheless, they are protected from diet-induced hepatic steatosis. As we observe constitutively elevated p-Akt levels in the adipocytes, even under conditions of low insulin levels, this pinpoints enhanced Ras-ERK-MAPK signaling in transgenic adipocytes as a potential alternative route to bypass proximal insulin signaling events. Conclusion We conclude that E4orf1 expression in the adipocyte leads to enhanced baseline activation of the distal insulin signaling node, yet impaired insulin receptor stimulation in the presence of insulin, with important implications for the regulation of adiponectin secretion. The resulting systemic phenotype is complex, yet highlights the powerful nature of manipulating selective branches of the insulin signaling network within the adipocyte.

Leptin Beyond the Lipostat: Key Component of Blood Pressure Regulation

Leptin Mediates the Increase in Blood Pressure Associated With Obesity nnSimonds et alnnCell . 2014;159:1404–1416nnObese individuals often struggle with increases in blood pressure (BP) that ultimately lead to an enhanced cardiovascular disease (CVD) risk. The mechanistic basis for this association has remained largely unknown. Although a large number of metabolic signals are altered in obese individuals, including dyslipidemia, associated changes in sphingolipids, and an overall increase in subclinical inflammation, none of these parameters are thought to greatly influence BP. Recent data suggest that the adipokine leptin, whose circulating levels are typically proportional to fat mass, is a major driving force for the obesity-associated increases in BP. The effects of leptin on BP are mediated by neuronal circuits, including leptin-responsive neurons in the dorsomedial hypothalamic (DMH) nucleus. nnObesity is a widespread global health burden. It is intuitively obvious that obesity is a direct consequence of an imbalance between energy intake and energy expenditure, resulting in gross expansion of adipose tissue and an associated increase in BP, which is a major contributor to chronic hypertension and the risk for CVD-related mortality. The obese state is associated with dysfunctional adipose tissue exhibiting an abnormal secretory profile of bioactive adipokines1; this contributes to impaired regulation of appetite, an unfavorable adipose tissue distribution, reduced insulin sensitivity, endothelial dysfunction, inflammation, and an elevation in BP.1nnLast year marked the 20th anniversary since the discovery of leptin from rodent adipose tissue in 1994 by Zhang et al.2 This discovery, along with the initial description of adiponectin around the same time, ignited a wealth of interest in adipose tissue as an endocrine organ and, in the case of leptin, enhanced our understanding in the biology of appetite and the maintenance of body weight control in obesity. Leptin is a pleiotropic hormonal signal …

The effects adiposity, diabetic status and depot-specificity on the activation of NFKB on JNK in human abdominal adipose tissue

The President reported that ‘The case for a UN resolution’ had been prepared by the IDF to highlight the need for a United Nations Resolution on diabetes in order to focus attention on the need to stop the growing diabetes epidemic. Dr. Ferrannini reported that ISPAD was a small, but enthusiastic organisation which had recently held a very well-attended meeting in Cambridge, UK. Following information that pediatricians are not attending the EASD Annual Meetings, discussions to organise a pediatric track in the programme of the Annual Meeting have been put forward. Dr. DahlJørgensen has also suggested organising a joint EASD/ ISPAD Postgraduate Course on Pediatric Diabetes in Europe in 2008. The President reported that a joint statement with ADA on guidelines on the treatment of type 2 diabetes was simultaneously published in August in both Diabetologia and Diabetes Care. Drs. R.J. Heine and R. Holman lead an ad-hoc committee from the EASD which also included Dr. S. del Prato and Dr. U. Smith. More details on EASD and EFSD activities were reported in the President’s Address given before the Minkowski Lecture, which is available on the internet under: http://www.easd-lectures.org/copenhagen/index. php?menu=lectures&id=66 and in his speech before the 38th Claude Bernard Lecture, available under: http://www.easd-lectures.org/copenhagen/index. php?menu=lectures&id=72 The President welcomed everyone to the 42nd General Assembly.Type III phosphatidylinositol 4-kinases mediate plasma membrane PIP2 synthesis in insulin-secreting cells