We propose that energy balance, glucose homeostasis, and aging are all regulated largely by the same nutrient-sensing neurons in the ventromedial hypothalamus (VMH)., Although the central role of these neurons in regulating energy balance is clear, their role in regulating glucose homeostasis has only become more clear recently. It is the latter function that may be most relevant to aging and lifespan, by controlling the rate of glucose metabolism. Specifically, glucose-sensing neurons in VMH promote peripheral glucose metabolism, and dietary restriction, by reducing glucose metabolism in these neurons, reduces glucose metabolism of the rest of the body, thereby increasing lifespan. Here we discuss recent studies demonstrating the key role of hypothalamic neurons in driving aging and age-related diseases.
Lifespan; glucose metabolism; dietary restriction
An inability of adipose tissue to expand consequent to exhausted capacity to recruit new adipocytes might underlie the association between obesity and insulin resistance. Adipocytes arise from mesenchymal precursors whose commitment and differentiation along the adipocytic lineage is tightly regulated. These regulatory factors mediate cross-talk between adipose cells, ensuring that adipocyte growth and differentiation are coupled to energy storage demands. The WNT family of autocrine and paracrine growth factors regulates adult tissue maintenance and remodelling and, consequently, is well suited to mediate adipose cell communication. Indeed, several recent reports, summarized in this review, implicate WNT signalling in regulating adipogenesis. Manipulating the WNT pathway to alter adipose cellular makeup, therefore, constitutes an attractive drug-development target to combat obesity-associated metabolic complications.
Atherosclerosis is characterized by the progressive accumulation of lipids and leukocytes in the arterial wall. Leukocytes such as macrophages accumulate oxidized lipoproteins in the growing atheromata and give rise to foam cells, which can then contribute to a lesion’s necrotic core. Lipids and leukocytes interact also in other important ways. In experimental models, systemic hypercholesterolemia is associated with severe neutrophilia and monocytosis. Recent evidence indicates that cholesterol sensing pathways control the proliferation of hematopoietic stem cell progenitors. Here we review some of the studies that are forging this particular link between metabolism and inflammation and propose several strategies that could target this axis for the treatment of cardiovascular disease.
hypercholesterolemia; atherosclerosis; hematopoietic stem and progenitor cells; monocytes; neutrophils
The discovery of the receptor for advanced glycation endproducts (RAGE) set the stage for the elucidation of important mechanisms underpinning diabetic complications. RAGE transduces the signals of advanced glycation endproducts, pro-inflammatory S100/calgranulins and high mobility group box 1 (HMGB1), and is a one of a family of receptors for lysophosphatidic acid (LPA). These ligand tales weave a theme of vascular perturbation and inflammation linked to the pathogenesis of the chronic complications of diabetes. Once deemed implausible, this concept of inflammatory cues participating in diabetic complications is now supported by a plethora of experimental evidence in the macro- and microvasculature. We review the biology of ligand-RAGE signal transduction and its roles in diabetic microvascular complications, from animal models to human subjects.
diabetes; ligands; inflammation; complications; receptor for AGE
Lipoproteins in plasma transport lipids between tissues, however, only high density lipoproteins (HDL) appear to traverse the blood brain barrier; thus, lipoproteins found in the brain must be produced within the central nervous system. Apolipoproteins E (ApoE) and ApoJ are the most abundant apolipoproteins in the brain, are mostly synthesized by astrocytes and are found on HDL. In the hippocampus and other brain regions lipoproteins help regulate neurobehavioral functions by processes that are lipoprotein receptor-mediated. Moreover, lipoproteins and their receptors also have roles in the regulation of body weight and energy balance, i.e. through lipoprotein lipase (LPL) and the LDL receptor-related protein (LRP). Thus, understanding lipoproteins and their metabolism in the brain provides a new opportunity with potential therapeutic relevance.
lipoprotein; metabolism; brain; lipoprotein receptor; neuron; astrocyte
Traditionally, the ketone body β-hydroxybutyrate (βOHB) has been looked upon as a carrier of energy from liver to peripheral tissues during fasting or exercise. However, βOHB also signals via extracellular receptors and acts as an endogenous inhibitor of histone deacetylases (HDACs). These recent findings support a model in which βOHB functions to link the environment, in this case the diet, and gene expression via chromatin modifications. Here, we review the regulation and functions of ketone bodies, the relationship between ketone bodies and calorie restriction, and the implications of HDAC inhibition by the ketone body βOHB in the modulation of metabolism, and diseases of aging.
acetylation; HDAC; calorie restriction; longevity; epigenetics
Progranulin is a widely expressed, cysteine-rich, secreted glycoprotein originally discovered for its growth factor–like properties. Its subsequent identification as a causative gene for frontotemporal dementia (FTD), a devastating early-onset neurodegenerative disease, has catalyzed a surge of new discoveries about progranulin’s function in the brain. More recently, progranulin was recognized as an adipokine involved in diet-induced obesity and insulin resistance, revealing its metabolic function. Here, we review progranulin biology in both neurodegenerative and metabolic diseases. In particular, we highlight progranulin’s growth factor–like, trophic, and anti-inflammatory properties as potential unifying themes in these seemingly divergent conditions. We also discuss potential therapeutic options for raising progranulin levels to treat progranulin-deficient FTD, as well as the possible consequences of such treatment.
Autophagy classically functions as a physiological process to degrade cytoplasmic components, protein aggregates, and/or organelles, as a mechanism for nutrient breakdown, and as a regulator of cellular architecture. Proper autophagic flux is vital for both functional skeletal muscle, which controls support and movement of the skeleton, and muscle metabolism. The role of autophagy as a metabolic regulator in muscle has been previously studied; however, the underlying molecular mechanisms that control autophagy in skeletal muscle have only just begun to emerge. Here, we review recent literature on the molecular pathways controlling skeletal muscle autophagy, and discuss how they connect autophagy to metabolic regulation. We also focus on the implications these studies hold for understanding metabolic and muscle wasting diseases.
Hypoglycemia produces complex neural and hormonal responses that restore glucose levels to normal. Glucose, metabolic substrates and their transporters, neuropeptides and neurotransmitters alter the firing rate of glucose sensing neurons in the ventromedial hypothalamus (VMH) which monitor energy status and regulate the release of neurotransmitters that instigate a suitable counterregulatory response. Under normal physiological conditions, these mechanisms maintain blood glucose concentrations within narrow margins. However, antecedent hypoglycemia and diabetes can lead to adaptations within the brain that impair counterregulatory responses. Clearly, the mechanisms employed to detect and regulate the response to hypoglycemia and the pathophysiology of defective counterregulation in diabetes are complex and need to be elucidated so therapies can be developed to prevent or reduce the risk of hypoglycemia.
brain; glucose sensing; diabetes; recurrent hypoglycemia; ventromedial hypothalamus; hypoglycemia
Obesity has increased at an alarming rate in recent years and is now a worldwide public health problem. Elucidating the mechanisms behind the metabolic dysfunctions associated with obesity is of high priority. The metabolic function of Rho-kinase (ROCK) has been the subject of a great deal of investigation in metabolic-related diseases. It appears that inhibition of ROCK activity is beneficial for the treatment of a wide range of cardiovascular-related diseases. However, recent studies with genetic models of ROCK demonstrate that ROCK plays a positive role in insulin and leptin signaling. Here we discuss the newly identified functions of ROCK in regulating glucose and energy metabolism, with particularly emphasis on metabolic actions of insulin and leptin.
Rho-kinase; glucose metabolism; insulin action; energy homeostasis; leptin action
Steroid hormone receptors (SHRs) are hormone-activated transcription factors involved in numerous cellular functions and in health and disease. Their activities depend on the cellular level of the receptor, the presence of coregulator proteins and the cell signaling pathways that are active in the cell. SHRs and their coregulators are phosphorylated on multiple sites by a wide variety of kinases. Each site may contribute to multiple functions and the net effect of an individual phosphorylation depends on the activating kinase. Here we discuss functions of known SHR phosphorylation sites, kinase regulation, evidence of translational relevance, and cross-talk between SHRs and cell signaling pathways. Understanding how cell signaling pathways regulate SHRs might yield novel therapeutic targets for multiple human diseases.
steroid receptor; phosphorylation; coactivator; cell signaling
In advanced age, the resting myocardial oxygen consumption (M V̇O2) and cardiac work (CW) in the rat remain intact. However, M V̇O2, CW and cardiac efficiency achieved at high demand are decreased with age, compared to maximal values in the young. Whether this deterioration is due to decrease in myocardial ATP demand, ATP supply, or the control mechanisms that match them, remains controversial. Here we discuss evolving perspectives of age-related changes of myocardial ATP supply and demand mechanisms, and critique experimental models used to investigate aging. Specifically, we evaluate experimental data collected at the level of isolated mitochondria, tissue, or organism, and discuss how mitochondrial energetic mechanisms change in advanced age, both at basal and high energy demand levels.
Aging; cardiac work; bioenergetics; mitochondria; respiration
In recent years, distinct signaling pathways involving specific complexes of cytoplasmic proteins have been shown to orchestrate estrogen action. These pathways might supplement or augment genomic effects of estrogen that are attributable to transcriptional activation by liganded receptor. Signals might be transduced through phosphorylation of the estrogen receptors (ERs), or indirectly through effects upon transcriptional coactivators or cell receptors. Estrogen signaling is coupled to growth factor signaling with feedback mechanisms directly impacting function of growth factor receptors. These signaling pathways regulate important physiological processes, such as cell growth and apoptosis. Here, we focus on cytoplasmic signaling pathways leading to activation of ERs.
Replacement of insulin-producing cells is a promising therapy for the restoration of the beta cell mass that is destroyed in patients with type 1 diabetes (T1D). However, the use of large amounts of islets per transplant, coupled with the scarcity of donor tissue, diminishes its feasibility. Here we briefly discuss current progress in developing ideal functional beta cells as well as the rationale for developing renewable sources of insulin-producing cells that can be transplanted.
type 1 diabetes; islet cell transplantation; beta cells; induced pluripotent stem cell; embryonic stem cell
The negative impact of consuming sugar-sweetened beverages on weight and other health outcomes has been increasingly recognized; therefore, many people have turned to high-intensity sweeteners like aspartame, sucralose, and saccharin as a way to reduce the risk of these consequences. However, accumulating evidence suggests that frequent consumers of these sugar substitutes may also be at increased risk of excessive weight gain, metabolic syndrome, type 2 diabetes, and cardiovascular disease. This paper discusses these findings and considers the hypothesis that consuming sweet-tasting but noncaloric or reduced-calorie food and beverages interferes with learned responses that normally contribute to glucose and energy homeostasis. Because of this interference, frequent consumption of high-intensity sweeteners may have the counterintuitive effect of inducing metabolic derangements.
obesity; diabetes; sweeteners
Remarkable progress in recent years has suggested that estrogen action in vivo is complex and often involves activation of cytoplasmic signaling cascades in addition to genomic actions mediated directly through estrogen receptors α and β. Rather than a linear response mediated solely through estrogen-responsive DNA elements, in vivo estrogen might simultaneously activate distinct signaling cascades that function as networks to coordinate tissue responses to estrogen. This complex signaling system provides for exquisite control and plasticity of response to estrogen at the tissue level, and undoubtedly contributes to the remarkable tissue-specific responses to estrogens. In part I of this series, we summarize cytoplasmic signaling modules involving estrogen or estrogen receptors, with particular focus on recently described membrane-associated signaling complexes.
Mitochondrial diseases encompass a wide range of presentations and mechanisms, dictating a need to consider both broad-based and disease-specific therapies. The manifestations of mitochondrial dysfunction and the response to therapy vary between individuals. This probably reflects the genetic complexity of mitochondrial biology, which requires an excess of 2000 genes for proper function, with numerous interfering epigenetic and environmental factors. Accordingly, we are increasingly aware of the complexity of these diseases which involve far more than merely decreased ATP supply. Indeed, recent therapeutic progress has addressed only specific disease entities. In this review present and prospective therapeutic approaches will be discussed on the basis of targets and mechanism of action, but with a broad outlook on their potential applications.
mitochondrial therapy; clinical trials; idebenone; MNGIE
Nescient helix loop helix 2 (NSCL2/NHLH2) is a neuronal transcription factor originally thought to be involved in neuronal development and childhood neuroblastomas. Accumulating evidence has since identified roles for NHLH2 in adult phenotypes of obesity and fertility. Here, we summarize these findings, and attempt to link genotype with phenotype in mouse models and humans. In particular, NHLH2 (Nhlh2 in mice) is one of only two genes that are genetically linked to physical activity levels. Nhlh2 also controls obesity and fertility, with strong sexual dimorphism displayed for both phenotypes by Nhlh2 mutant animals. We propose that Nhlh2 might function as a molecular sensor in different adult hypothalamic neurons to regulate energy balance, leading to normal body weight and reproduction.
reproduction; exercise; body weight; sexual behavior; transcription
The leading cause of death in diabetic patients is cardiovascular disease. Apolipoprotein B (ApoB)-containing lipoprotein particles, which are secreted and cleared by the liver, are essential for the development of atherosclerosis. Insulin plays a key role in the regulation of ApoB. Insulin decreases ApoB secretion by promoting ApoB degradation in the hepatocyte. In parallel, insulin promotes clearance of circulating ApoB particles in the liver via the low density lipoprotein receptor (LDLR), LDLR-related protein 1 (LRP1), and heparan sulfate proteoglycans (HSPGs). Consequently, the insulin resistant state of Type 2 diabetes (T2D) is associated with increased secretion and decreased clearance of ApoB. Here, we review the mechanisms by which insulin controls the secretion and uptake of ApoB in normal and diabetic livers.
apolipoprotein B; insulin; diabetes; very low density lipoprotein (VLDL); cardiovascular disease; selective insulin resistance