Adipose mTORC2 is essential for arborization of sensory neurons in white adipose tissue and whole-body energy homeostasis

Adipose tissue, via sympathetic and sensory neurons, communicates with the central nervous system (CNS) to mediate energy homeostasis. In contrast to the sympathetic nervous system, the morphology, role and regulation of the sensory nervous system in adipose tissue is poorly characterized. Taking advantage of recent progress in whole-mount three-dimensional imaging of adipose tissue, we identified a neuronal network of calcitonin gene-related protein (CGRP)-positive sensory neurons in white adipose tissue (WAT). Furthermore, we show that adipose mammalian target of rapamycin complex 2 (mTORC2), a major component of the insulin signaling pathway, mediates sensory innervation in WAT. Based on visualization of neuronal networks, mTORC2-deficient WAT displayed reduced arborization of (CGRP)-positive sensory neurons, while sympathetic neurons were unaffected. This selective loss of sensory innervation followed reduced expression of growth-associated protein 43 (GAP43) in CGRP-positive sensory neurons. Finally, we found that loss of sensory innervation in WAT correlated with systemic insulin resistance. Our findings suggest that adipose mTORC2 is necessary for sensory innervation in WAT which likely contributes to WAT-to-CNS communication

Adipose mTORC2 is essential for sensory innervation in white adipose tissue and whole-body energy homeostasis

Adipose tissue, via sympathetic and possibly sensory neurons, communicates with the central nervous system (CNS) to mediate energy homeostasis. In contrast to the sympathetic nervous system, the morphology, role and regulation of the sensory nervous system in adipose tissue are poorly characterized.; Taking advantage of recent progress in whole-mount three-dimensional imaging, we identified a network of calcitonin gene-related protein (CGRP)-positive sensory neurons in murine white adipose tissue (WAT). We found that adipose mammalian target of rapamycin complex 2 (mTORC2), a major component of the insulin signaling pathway, is required for arborization of sensory, but not of sympathetic neurons. Time course experiments revealed that adipose mTORC2 is required for maintenance of sensory neurons. Furthermore, loss of sensory innervation in WAT coincided with systemic insulin resistance. Finally, we established that neuronal protein growth-associated protein 43 (GAP43) is a marker for sensory neurons in adipose tissue.; Our findings indicate that adipose mTORC2 is necessary for sensory innervation in WAT. In addition, our results also suggest that WAT may affect whole-body energy homeostasis via sensory neurons

Diet-induced loss of adipose Hexokinase 2 triggers hyperglycemia

Chronically high blood glucose (hyperglycemia) leads to diabetes, fatty liver disease, and cardiovascular disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. Here we show that a high fat diet (HFD) in mice causes early loss of expression of the glycolytic enzyme Hexokinase 2 (HK2) specifically in adipose tissue. Adipose-specific knockout of Hk2 caused enhanced gluconeogenesis and lipogenesis in liver, a condition known as selective insulin resistance, leading to glucose intolerance. Furthermore, we observed reduced hexokinase activity in adipose tissue of obese and diabetic patients, and identified a loss-of-function mutation in the hk2 gene of naturally hyperglycemic Mexican cavefish. Mechanistically, HFD in mice led to loss of HK2 by inhibiting translation of Hk2 mRNA. Our findings identify adipose HK2 as a critical mediator of systemic glucose homeostasis, and suggest that obesity-induced loss of adipose HK2 is an evolutionarily conserved, non-cell-autonomous mechanism for the development of hyperglycemia

Insulin resistance causes inflammation in adipose tissue

Obesity is a major risk factor for insulin resistance and type 2 diabetes. In adipose tissue, obesity-mediated insulin resistance correlates with the accumulation of proinflammatory macrophages and inflammation. However, the causal relationship of these events is unclear. Here, we report that obesity-induced insulin resistance in mice precedes macrophage accumulation and inflammation in adipose tissue. Using a mouse model that combines genetically induced, adipose-specific insulin resistance (mTORC2-knockout) and diet-induced obesity, we found that insulin resistance causes local accumulation of proinflammatory macrophages. Mechanistically, insulin resistance in adipocytes results in production of the chemokine monocyte chemoattractant protein 1 (MCP1), which recruits monocytes and activates proinflammatory macrophages. Finally, insulin resistance (high homeostatic model assessment of insulin resistance [HOMA-IR]) correlated with reduced insulin/mTORC2 signaling and elevated MCP1 production in visceral adipose tissue from obese human subjects. Our findings suggest that insulin resistance in adipose tissue leads to inflammation rather than vice versa

Hepatic mTORC2 compensates for loss of adipose mTORC2 in mediating energy storage and glucose homeostasis

Mammalian target of rapamycin complex 2 (mTORC2) is a protein kinase complex that plays an important role in energy homeostasis. Loss of adipose mTORC2 reduces lipogenic enzyme expression and de novo lipogenesis in adipose tissue. Adipose-specific mTORC2 knockout mice also display triglyceride accumulation in the liver. However, the mechanism and physiological role of hepatic triglyceride accumulation upon loss of adipose mTORC2 are unknown. Here, we show that loss of adipose mTORC2 increases the expression of de novo lipogenic enzymes in the liver, thereby causing accumulation of hepatic triglyceride and hypertriglyceridemia. Simultaneous inhibition of lipogenic enzymes in adipose tissue and liver by ablating mTORC2 in both tissues prevented accumulation of hepatic triglycerides and hypertriglyceridemia. However, loss of adipose and hepatic mTORC2 caused severe insulin resistance and glucose intolerance. Thus our findings suggest that increased hepatic lipogenesis is a compensatory mechanism to cope with loss of lipogenesis in adipose tissue, and further suggest that mTORC2 in adipose tissue and liver plays a crucial role in maintaining whole body energy homeostasis.; NEW & NOTEWORTHY; Loss of adipose and hepatic mTORC2 causes diabetes

Wandel verstehen, Zukunft gestalten : Impulse für die Zukunft der Innovation

Die Dynamik der wirtschaftlichen Entwicklung und deren Abhängigkeit von globalen Wechselwirkungen wachsen heute schneller denn je. Das macht Zukunftsprognosen besonders schwierig. Dennoch bietet der Blick auf langfristig prägende Trends die Chance, eine Diskussion darüber zu eröffnen, welche Realität uns morgen erwarten könnte und wie wir damit umgehen wollen. Dieses Impulspapier stellt aus Sicht der Mitgliedsinstitute des Fraunhofer Verbunds Innovationsforschung eine Auswahl derjenigen Trends dar, die Innovationssysteme im Zeitraum bis 2030 wesentlich beeinflussen werden. Auf dieser Grundlage werden Thesen für Innovation im Jahr 2030 abgeleitet und beschrieben, welche Aufgaben sich daraus für Wirtschaft, Politik, Wissenschaft und Gesellschaft ergeben

Wandel verstehen - Zukunft gestalten: Impulse für die Zukunft der Innovation

Die Dynamik der wirtschaftlichen Entwicklung und deren Abhängigkeit von globalen Wechselwirkungen wachsen heute schneller denn je. Das macht Zukunftsprognosen besonders schwierig. Dennoch bietet der Blick auf langfristig prägende Trends die Chance, eine Diskussion darüber zu eröffnen, welche Realität uns morgen erwarten könnte und wie wir damit umgehen wollen. Dieses Impulspapier stellt aus Sicht der Mitgliedsinstitute des Fraunhofer-Verbunds Innovationsforschung eine Auswahl derjenigen Trends dar, die Innovationssysteme im Zeitraum bis 2030 wesentlich beeinflussen werden. Auf dieser Grundlage werden Thesen für Innovation im Jahr 2030 abgeleitet und beschrieben, welche Aufgaben sich daraus für Wirtschaft, Politik, Wissenschaft und Gesellschaft ergeben

Understanding change, shaping the future : impulses for the future of innovation

The unprecedented acceleration in the dynamics of economic development and its dependence on global interactions makes predicting the future especially difficult. Nevertheless, an examination of long-term trends provides an opportunity to begin a discussion about what reality could await us tomorrow and how we want to deal with it. With this food-for-thought paper, the member institutes of the Fraunhofer Group for Innovation Research wish to present a selection of the trends that are destined to have a significant impact on innovation systems in the period leading up to 2030. Based on these trends, the paper derives theses for innovation in the year 2030 and describes the resulting tasks for business, politics, science and society

Comprendre le changement - construire l'avenir: Des réflexions sur l'avenir de l'innovation

L’accélération sans précédent de la dynamique du développement économique et de sa dépendance par rapport aux interactions mondiales rend les prédictions particulièrement difficiles. Néanmoins, l’analyse des tendances à long terme permet d’ouvrir une discussion sur les réalités qui pourraient nous attendre compte tenu des tendances à long terme, il convient d’ouvrir le débat sur les réalités de demain et sur la manière dont nous voulons les gérer. Les instituts du Fraunhofer-Verbund Innovationsforschung souhaitent présenter dans ce document de réflexion une sélection des principales tendances susceptibles d’influencer significativement les systèmes d’innovation d’ici à 2030. Sur la base de ces tendances, ce document tire des enseignements des thèses sur l’innovation d’ici à 2030 et décrit la nature des tâches qui en résulteront pour le monde économique, politique, scientifique et social

Diet-induced loss of adipose hexokinase 2 correlates with hyperglycemia

Chronically high blood glucose (hyperglycemia) leads to diabetes and fatty liver disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. Here, we show that a high-fat diet (HFD) in mice causes early loss of expression of the glycolytic enzyme Hexokinase 2 (HK2) specifically in adipose tissue. Adipose-specific knockout of Hk2 reduced glucose disposal and lipogenesis and enhanced fatty acid release in adipose tissue. In a non-cell-autonomous manner, Hk2 knockout also promoted glucose production in liver. Furthermore, we observed reduced hexokinase activity in adipose tissue of obese and diabetic patients, and identified a loss-of-function mutation in the hk2 gene of naturally hyperglycemic Mexican cavefish. Mechanistically, HFD in mice led to loss of HK2 by inhibiting translation of Hk2 mRNA. Our findings identify adipose HK2 as a critical mediator of local and systemic glucose homeostasis, and suggest that obesity-induced loss of adipose HK2 is an evolutionarily conserved mechanism for the development of selective insulin resistance and thereby hyperglycemia