There are three dominant contributors to the pathogenesis of dysfunctional adipose tissue (AT) in obesity: unresolved inflammation, inappropriate extracellular matrix (ECM) remodeling and insufficient angiogenic potential. The interactions of these processes during AT expansion reflect both a linear progression as well as feed-forward mechanisms. For example, both inflammation and inadequate angiogenic remodeling can drive fibrosis, which can in turn promote migration of immune cells into adipose depots and impede further angiogenesis. Therefore, the relationship between the members of this triad is complex but important for our understanding of the pathogenesis of obesity. Here we untangle some of these intricacies to highlight the contributions of inflammation, angiogenesis, and the ECM to both "healthy" and "unhealthy" AT expansion.

Summary We have uncovered the existence of extracellular vesicle (EV)-mediated signaling between cell types within the adipose tissue (AT) proper. This phenomenon became evident in our attempts at generating an adipocyte-specific knock out of caveolin 1 (cav1) protein. While we effectively ablated the CAV1 gene in adipocytes, cav1 protein remained abundant. With the use of newly generated mouse models, we show that neighboring endothelial cells (ECs) transfer cav1-containing EVs to adipocytes in vivo, which reciprocate by releasing EVs to ECs. AT-derived EVs contain proteins and lipids capable of modulating cellular signaling pathways. Furthermore, this mechanism facilitates transfer of plasma constituents from ECs to the adipocyte. The transfer event is physiologically regulated by fasting/refeeding and obesity, suggesting EVs participate in the tissue response to changes in the systemic nutrient state. This work offers new insights into the complex signaling mechanisms that exist between adipocytes, stromal vascular cells and potentially distal organs.

No abstract

No abstract

Cardiac function depends on the ability to switch between fatty acid and glucose oxidation for energy production in response to changes in substrate availability and energetic stress. In obese and diabetic individuals, increased reliance on fatty acids and reduced metabolic flexibility are thought to contribute to the development of cardiovascular disease. Mechanisms by which cardiac mitochondria contribute to diet-induced metabolic inflexibility were investigated. Mice were fed a high fat or low fat diet for 1 d, 1 wk, and 20 wk. Cardiac mitochondria isolated from mice fed a high fat diet displayed a diminished ability to utilize the glycolytically derived substrate pyruvate. This response was rapid, occurring within the first day on the diet, and persisted for up to 20 wk. A selective increase in the expression of pyruvate dehydrogenase kinase 4 and inhibition of pyruvate dehydrogenase are responsible for the rapid suppression of pyruvate utilization. An important consequence is that pyruvate dehydrogenase is sensitized to inhibition when mitochondria respire in the presence of fatty acids. Additionally, increased expression of pyruvate dehydrogenase kinase 4 preceded any observed diet-induced reductions in the levels of glucose transporter type 4 and glycolytic enzymes and, as judged by Akt phosphorylation, insulin signaling. Importantly, diminished insulin signaling evident at 1 wk on the high fat diet did not occur in pyruvate dehydrogenase kinase 4 knockout mice. Dietary intervention leads to a rapid decline in pyruvate dehydrogenase kinase 4 levels and recovery of pyruvate dehydrogenase activity indicating an additional form of regulation. Finally, an overnight fast elicits a metabolic response similar to that induced by high dietary fat obscuring diet-induced metabolic changes. Thus, our data indicate that diet-induced inhibition of pyruvate dehydrogenase may be an initiating event in decreased oxidation of glucose and increased reliance of the heart on fatty acids for energy production.

No abstract

Edited by George N. DeMartinoCardiac metabolic inflexibility is driven by robust up-regulation of pyruvate dehydrogenase kinase 4 (PDK4) and phosphorylation-dependent inhibition of pyruvate dehydrogenase (PDH) within a single day of feeding mice a high fat diet. In the current study, we have discovered that PDK4 is a short lived protein (t1 ⁄ 2 ϳ 1 h) and is specifically degraded by the mitochondrial protease Lon. Lon does not rapidly degrade PDK1 and -2, indicating specificity toward the PDK isoform that is a potent modulator of metabolic flexibility. Moreover, PDK4 degradation appears regulated by dissociation from the PDH complex dependent on the respiratory state and energetic substrate availability of mouse heart mitochondria. Finally, we demonstrate that pharmacologic inhibition of PDK4 promotes PDK4 degradation in vitro and in vivo. These findings reveal a novel strategy to manipulate PDH activity by selectively targeting PDK4 content through dissociation and proteolysis.Dynamic regulation of metabolism is required for cells to respond to nutrient availability and stress to support ATP production and anabolic processes. Misappropriated metabolic alterations can exert deleterious effects as evidenced in diabetes and in many cancers where the preference for a specific metabolic profile promotes the progression of disease (1, 2). The heart derives energy primarily from the oxidation of fatty acids. However, glucose utilization increases with enhanced availability and is essential for cardiac function, particularly in response to physiologic and pathophysiologic stress. Obesity and diabetes are characterized by heavy reliance of the heart on fatty acids for energy production and the inability to appropriately utilize glucose (1). Loss of metabolic flexibility is believed to underlie associated cardiovascular disease. In mouse models of diet-induced obesity, induction of cardiac metabolic inflexibility has long been attributed to insulin resistance and altered glucose transporter 4 expression and transport (1, 3). However, we have recently made the discovery that these events are preceded by diminished mitochondrial oxidation of glucose-derived pyruvate, occurring within the 1st day of high fat feeding (4).The mitochondrial enzyme pyruvate dehydrogenase (PDH) 2 commits glycolytically derived pyruvate for ATP production and is central to regulating the use of glucose relative to fatty acids for energy homeostasis. Cardiac PDH activity is regulated by various isoforms of pyruvate dehydrogenase kinase (PDK1, -2, and -4) and phosphatase (PDP1 and -2) with phosphorylation resulting in enzyme inhibition (5-7). We demonstrated that a selective increase in cardiac PDK4 expression and inhibition of PDH are responsible for the rapid diet-induced loss of mitochondrial pyruvate utilization and the ensuing development of insulin resistance in the heart (4). Given that PDK4-mediated inhibition of PDH is an initiating event in diet-induced metabolic inflexibility and PDH is a key site for control of glucose oxidation, it is ...

Rindler PM, Crewe CL, Fernandes J, Kinter M, Szweda LI. Redox regulation of insulin sensitivity due to enhanced fatty acid utilization in the mitochondria. Am J Physiol Heart Circ Physiol 305: H634 -H643, 2013. First published June 21, 2013; doi:10.1152/ajpheart.00799.2012.-Obesity enhances the risk for the development of type 2 diabetes and cardiovascular disease. Loss in insulin sensitivity and diminished ability of muscle to take up and use glucose are characteristics of type 2 diabetes. Paradoxically, regulatory mechanisms that promote utilization of fatty acids appear to initiate diet-induced insulin insensitivity. In this review, we discuss recent findings implicating increased mitochondrial production of the prooxidant H 2O2 due to enhanced utilization of fatty acids, as a signal to diminish reliance on glucose and its metabolites for energy. In the short term, the ability to preferentially use fatty acids may be beneficial, promoting a metabolic shift that ensures use of available fat by skeletal muscle and heart while preventing intracellular glucose accumulation and toxicity. However, with prolonged consumption of high dietary fat and ensuing obesity, the near exclusive dependence on fatty acid oxidation for production of energy by the mitochondria drives insulin resistance, diabetes, and cardiovascular disease. mitochondria; metabolic flexibility; redox signaling; insulin signaling; obesity THIS ARTICLE is part of a collection on Mitochondria in Cardiovascular Physiology and Disease. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at http://ajpheart.physiology.org/.