A healthy pregnancy requires strict coordination of genetic, physiologic, and environmental factors. The relatively common incidence of infertility and pregnancy complications has resulted in increased interest in understanding the mechanisms that underlie normal versus abnormal pregnancy. The peptide hormone adrenomedullin has recently been the focus of some exciting breakthroughs in the pregnancy field. Supported by mechanistic studies in genetic animal models, there continues to be a growing body of evidence demonstrating the importance of adrenomedullin protein levels in a variety of human pregnancy complications. With more extensive mechanistic studies and improved consistency in clinical measurements of adrenomedullin, there is great potential for the development of adrenomedullin as a clinically-relevant biomarker in pregnancy and pregnancy complications.
While 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 for cellular homeostasis of the adipocyte, and their impact on systemic energy homeostasis. A better understanding of the regulatory role that white adipocyte mitochondria play on whole body physiology becomes increasingly important. White adipose 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 esterification and lipogenesis, as well as their impact on production and release of key adipokines, mitochondria exert a critical role on systemic insulin sensitivity.
Gene regulatory factors encoded by the nuclear genome are essential for mitochondrial biogenesis and function. Some of these factors act exclusively within the mitochondria to regulate the control of mitochondrial transcription, translation and other functions. Others govern the expression of nuclear genes required for mitochondrial metabolism and organelle biogenesis. The peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of transcriptional coactivators plays a major role in transducing and integrating physiological signals governing metabolism, differentiation and cell growth to the transcriptional machinery controlling mitochondrial functional capacity. Thus, the PGC-1 coactivators serve as a central component of the transcriptional regulatory circuitry that coordinately controls the energy-generating functions of mitochondria in accordance with the metabolic demands imposed by changing physiological conditions, senescence, and disease.
Mitochondria; Peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1); Peroxisome proliferator-activated receptor (PPAR); transcription; gene regulation; metabolism
Mitochondria are intracellular powerhouses that produce ATP and carry out diverse functions for cellular energy metabolism. While the maintenance of an optimal NAD/NADH ratio is essential for mitochondrial function, it has recently become apparent that the maintenance of the mitochondrial NAD pool also has critical importance. The biosynthesis, transport, and catabolism of NAD and its key intermediates play an important role in the regulation of NAD-consuming mediators, such as sirtuins, poly-ADP-ribose polymerases, and CD38/157 ectoenzymes, in intra- and extracellular compartments. Mitochondrial NAD biosynthesis is also modulated in response to nutritional and environmental stimuli. In this article, we discuss this dynamic regulation of NAD metabolism in mitochondria to shed light on the intimate connection between NAD and mitochondrial function.
The mammalian target of rapamycin complex 1 (mTORC1) has the ability to sense a variety of essential nutrients and respond by altering cellular metabolic processes. Hence, this protein kinase complex is poised to influence adaptive changes to nutrient fluctuations toward the maintenance of whole-body metabolic homeostasis. Defects in mTORC1 regulation, arising from either physiological or genetic conditions, are believed to contribute to the metabolic dysfunction underlying a variety of human diseases, including type 2 diabetes. We are just now beginning to gain insights into the complex tissue-specific functions of mTORC1. Here, we detail our current knowledge of the physiological functions of mTORC1 in controlling systemic metabolism, with a focus on advances obtained through genetic mouse models.
Maintaining blood glucose homeostasis is a complex process dependent on pancreatic islet hormone secretion. Hormone secretion from islets is coupled to calcium entry, which results from regenerative islet cell electrical activity. Therefore, the ionic mechanisms that regulate calcium entry into islet cells are critical to maintaining normal glucose homeostasis. Genome wide association studies have identified single nucleotide polymorphisms, including five located in or near ion channel or associated subunit genes, which show association with human diseases characterized by dysglycemia. This review focuses on polymorphisms and mutations in ion channel genes that are associated with perturbations in human glucose homeostasis and discusses their potential roles in modulating pancreatic islet hormone secretion.
Oxidative stress is linked to the production of reactive lipid aldehydes that non-enzymatically alkylate cysteine, histidine or lysine residues in a reaction termed protein carbonylation. Reactive lipid aldehydes and their derivatives are detoxified via a variety of phase I and phase II systems and when antioxidant defenses are compromised or oxidative conditions are increased protein carbonylation is increased. The resulting modification has been implicated as causative in a variety of metabolic states including neurodegeneration, muscle wasting, insulin resistance and aging. Although such modifications usually result in loss of protein function, protein carbonylation may be regulatory and activate signaling pathways involved in antioxidant biology and cellular homeostasis.
4-HNE; carbonylation; reactive lipid aldehydes; steatosis; neurodegeneration; metabolism
Nonalcoholic fatty liver disease (NAFLD) is a chronic disease with a histological spectrum ranging from steatosis alone, to nonalcoholic steatohepatitis (NASH). The latter is associated with an increased risk for progression to cirrhosis. Ceramides are a lipid species that exert biological effects through cellular proliferation, differentiation and cell death, and interact with several pathways involved in insulin resistance, oxidative stress, inflammation, and apoptosis, all of which are linked to NAFLD. Herein, we propose a mechanism through which ceramides contribute to the development of NAFLD and progression to NASH, due in part to second messenger effects via TNF-α. A better understanding of the role of ceramides in steatohepatitis has both diagnostic and therapeutic implications for the treatment of fatty liver disease.
Insulin resistance; obesity; sphingolipids; apoptosis; oxidative stress
The circadian system synchronizes behavioral and physiologic processes with daily changes in the external light-dark cycle, optimizing energetic cycles with the rising and setting of the sun. Molecular clocks are organized hierarchically, with neural clocks orchestrating the daily switch between periods of feeding and fasting, and peripheral clocks generating 24hr oscillations of energy storage and utilization. Recent studies indicate that clocks respond to nutrient signals, and that high-fat diet influences the period of locomotor activity under free-running conditions, a core property of the clock. A major goal is to identify the molecular basis for the reciprocal relationship between metabolic and circadian pathways. Here, we highlight the role of peptidergic hormones and macromolecules as nutrient signals integrating circadian and metabolic systems.
With a current prevalence of approximately 20%, smoking continues to impact negatively upon health. Tobacco or nicotine use influences the endocrine system, with important clinical implications. In this review we critically evaluate the literature concerning the impact of nicotine as well as tobacco use on several parameters of the endocrine system and on glucose and lipid homeostasis. Emphasis is on the effect of smoking on diabetes mellitus and obesity and the consequences of smoking cessation on these disorders. Understanding the effects of nicotine and cigarettes on the endocrine system and how these changes contribute to the pathogenesis of various endocrine diseases will allow for targeted therapies and more effective approaches for smoking cessation.
nicotine; cigarettes; pituitary; hormones; hypogonadism; addiction
Many aspects of metabolism exhibit daily rhythmicity under the control of endogenous circadian clocks, and disruptions in circadian timing result in dysfunctions associated with the metabolic syndrome. Nocturnin (Noc) is a robustly rhythmic gene that encodes a deadenylase thought to be involved in the removal of polyA tails from mRNAs. Mice lacking the Noc gene display resistance to diet-induced obesity and hepatic steatosis, due in part to reduced lipid trafficking in the small intestine. In addition, Noc appears to play important roles in other tissues and has been implicated in lipid metabolism, adipogenesis, glucose homeostasis, inflammation and osteogenesis. Therefore, Noc is a potential key post-transcriptional mediator in the circadian control of many metabolic processes.
Nocturnin; Ccrn4l; Circadian; Deadenylase; Post-transcriptional; Metabolic syndrome
Nutrient and energy metabolism in mammals exhibits strong diurnal rhythm that aligns with the body clock. Circadian regulation of metabolism is mediated through reciprocal signaling between the clock and metabolic regulatory networks. Recent work has demonstrated that autophagy is rhythmically activated in a clock-dependent manner. As autophagy is a conserved biological process that contributes to nutrient and cellular homeostasis, its cyclic induction may provide a novel link between clock and metabolism. This review discusses the mechanisms underlying circadian autophagy regulation, the role of rhythmic autophagy in nutrient and energy metabolism, and its implications in physiology and metabolic disease.
The past decade has witnessed an explosion in research into adipose tissue stem cells (ASCs), facilitated by their ease of isolation from white adipose tissue (WAT) and fueled by their therapeutic potential. Recent developments have extended ASC multipotency to include endodermal and ectodermal cell types, along with generation of induced pluripotent stem cells. This expanding multipotency has been paralleled by burgeoning translational applications, ranging from tissue engineering to anti-cancer therapy, that are currently subject to clinical trials. However, this promise is tempered by potential pitfalls, such as tumorigenicity, and is further undermined by lingering uncertainties regarding the very identity of ASCs. Confronting these issues will be essential if we are to bypass the pitfalls and develop the promises of ASCs.
Epigenetic mechanisms may contribute to the pathogenesis of complex diseases. Early or late environmental influences such as intrauterine malnutrition or sedentary lifestyle have been shown to lead to an increased risk of diabetes. Recently, epigenetic mechanisms were shown to be involved in endocrine cell differentiation and islet function. Genomic profiling of pancreatic islets in non-diabetic and diabetic states is needed in order to dissect the contribution of epigenetic mechanisms to the declining proliferation potential of β cells that we see with aging or the β-cell failure observed in diabetes. In-depth understanding of epigenetic landscapes can help to improve protocols for in vitro differentiation towards the β-cell fate, enhance β-cell proliferation, and lead to the discovery of novel therapeutic targets.
The classical visual and beta arrestins belong to a larger family of proteins that likely share structural similarity. Humans have an additional six related proteins sometimes termed the alpha-arrestins, whose functions are now emerging. Surprisingly, several alpha-arrestins play prominent roles in the regulation of metabolism and obesity. One alpha-arrestin, thioredoxin interacting protein (Txnip) has critical functions in regulating glucose uptake and glycolytic flux through the mitochondria. Another alpha-arrestin, Arrdc3, is linked to obesity in men and was recently identified in mice as a regulator of body mass, adiposity, and energy expenditure. Here we discuss recent evidence suggesting potential common themes for all arrestins, including physiological roles for classical arrestins in metabolism and functions of alpha-arrestins in receptor signaling and endocytosis.
MicroRNAs (miRNAs) are short, non-coding RNAs that generally base-pair within the 3′ untranslated region of target mRNAs causing translational inhibition and/or mRNA degradation. Estradiol (E2) and other estrogen receptor (ER) ligands suppress or stimulate miRNA expression in human breast cancer cells, endometrial cells, rat mammary gland, and mouse uterus and post-translationally regulate protein expression. Aberrant miRNA expression is implicated in estrogen-related breast and endometrial cancers and a number of miRNAs downregulate ERα. The role of estrogen-regulated miRNA expression, the target genes of these miRNAs, and the role of miRNAs in health and disease is a “hot” area of research that will yield new insight into molecular mechanisms of estrogen action.
Twenty-five years after it was identified as a circulating protein derived from the placenta but of unknown function, pregnancy-associated plasma protein-A (PAPP-A) was discovered to be a novel zinc metalloproteinase expressed by a variety of cell types. Great progress has been made in understanding the biology of PAPP-A and its regulation during recent years, especially in regard to physiological and pathophysiological inflammatory injury responses. But much remains to be learned about this complex protein and its potential clinical implications outside of pregnancy. In this article we address some of the outstanding questions about PAPP-A, in particular about its newly emerging role in the insulin-like growth factor (IGF) system.
More than 70 years after its initial report, caloric restriction stands strong as the most consistent non-pharmacological intervention increasing lifespan and protecting against metabolic disease. Among the different mechanisms by which caloric restriction may act, Sir2/SIRT1 (Silent information regulator 2/Silent information regulator T1) has gained major attention due to its ability to integrate the sensing of the metabolic status with adaptative transcriptional outputs. This review focuses on gathered evidence suggesting that Sir2/SIRT1 is a key mediator of the beneficial effects of caloric restriction and addresses the main questions that still need to be answered to consolidate this hypothesis.
Inadequate β-cell mass can lead to insulin insufficiency and diabetes. During times of prolonged metabolic demand for insulin, the endocrine pancreas can respond by increasing β-cell mass, both by increasing cell size and by changing the balance between β-cell proliferation and apoptosis. In this paper, we review recent advances in our understanding of the mechanisms that control the adaptive expansion of β-cell mass, focusing on the islet’s response to pregnancy, a physiological state of insulin resistance. Functional characterization of factors controlling both β-cell proliferation and survival might not only lead to the development of successful therapeutic strategies to enhance the response of the β-cell to increased metabolic loads, but also improve islet transplantation regimens.
The hypothalamus is a small structure located in the ventral diencephalon. Hypothalamic neurons sense changes in circulating metabolic cues (e.g.: leptin, insulin, glucose), and coordinate responses aimed at maintaining normal body weight and glucose homeostasis. Recent findings indicate that a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase (namely, SIRT1) expressed by hypothalamic neurons is crucial for mounting responses against diet-induced obesity and type 2 diabetes mellitus (T2DM). Here, the repercussions of these findings will be discussed and particular emphasis will be given to the potential exploitation of hypothalamic SIRT1 as a target for the treatment of the rapidly-spreading metabolic disorders of obesity and T2DM. The possible roles of hypothalamic SIRT1 on regulating metabolic ageing processes will also be addressed.
Hypothalamus; SIRT1; aging; metabolism; obesity; diabetes; insulin; skeletal muscle
Growth hormone (GH) and insulin-like growth factor-I (IGF-I) exert powerful influences on somatic growth, metabolism, and tissue repair, and have been implicated in aging and carcinogenesis. Since the formulation of the somatomedin hypothesis over 50 years ago, GH and IGF-I have been linked intimately to one another. Recent studies have established that GH potently stimulates IGF-I gene transcription, and through this mechanism controls production of IGF-I. A key mediator of the GH - IGF-I biosynthetic pathway is the latent transcription factor Stat5b. This review summarizes the potentially complex mechanistic relationship among GH action, Stat5b, and IGF-I gene activation, and suggests that Stat5b may have a broad role in mediating IGF-I gene regulation in response to diverse physiological inputs.
Although lipid metabolism and host defense are widely considered to be very divergent disciplines, compelling evidence suggests that host cell handling of self- and microbe-derived (e.g., lipopolysaccharide) lipids may have common evolutionary roots, and that they indeed may be inseparable processes. The innate immune response and the homeostatic network controlling cellular sterol levels are now known to reciprocally regulate one another, with important implications for several common diseases, including atherosclerosis. In the present review, we discuss recent discoveries that provide new insight into the bidirectional crosstalk between reverse cholesterol transport and innate immunity, and highlight the broader implications of these findings for therapeutic development.
It is now firmly established that estrogen and all sex steroid receptors exist in discrete cellular pools outside the nucleus. Estrogen receptors (ER) have been localized to the plasma membrane where both ERα and ERβ function in a wide variety of cells and organs. ERs have also been found in discrete cytoplasmic organelles including mitochondria and the endoplasmic reticulum. In ligand-dependent fashion, each ER pool contributes to the overall, integrated effects of estrogens producing biological outcomes. This review highlights the recent work establishing new roles and targets of membrane ER signaling. Such actions include prevention of vascular injury or cardiac hypertrophy, sexual behavior and pain perception mediated through the central nervous system, osteoblast survival, and fluid resorption in the colon.