GLP-1 (9-36)amide is the cleavage product of GLP-1(7-36) amide formed by the action of diaminopeptidyl peptidase-4 (Dpp4) and is the major circulating form in plasma. Whereas GLP-1(7-36)amide stimulates glucose-dependent insulin secretion, GLP-1(9-36)amide has only weak partial insulinotropic agonist activities on the GLP-1 receptor, but suppresses hepatic glucose production, exerts antioxidant cardioprotective actions, and reduces oxidative stress in vasculature tissues. These insulin-like activities suggest a role for GLP-1 (9-36)amide in the modulation of mitochondrial functions by mechanisms independent of the GLP-1 receptor. Here we discuss the current literature suggesting that GLP-1(9-36)amide is an active peptide with important insulin-like actions. These findings have implications in nutrient assimilation, energy homeostasis, obesity, and the use of Dpp4 inhibitors for the treatment of diabetes.
Almost half of the 48 human ATP binding cassette (ABC) transporter proteins are thought to facilitate the ATP-dependent translocation of lipids or lipid-related compounds. Such substrates include cholesterol, plant sterols, bile acids, phospholipids and sphingolipids. Mutations in a substantial number of the 48 human ABC transporters have been linked to human disease. Indeed the finding that 12 diseases have been associated with abnormal lipid transport and/or homeostasis, demonstrates the importance of this family of transporters in cell physiology. This review highlights the role of ABC transporters in lipid transport and movement, in addition to discussing their roles in cellular homeostasis and inherited disorders.
Lipid transport; intracellular; ABC transporter
In the last decade, islet inflammation has emerged as a contributor to the loss of functional β cell mass in both type 1 (T1D) and type 2 diabetes (T2D). Evidence supports that over-nutrition and insulin resistance result in the production of proinflammatory mediators by β cells. In addition to compromising β cell function and survival, cytokines may recruit macrophages into islets, thus augmenting inflammation. Limited, but intriguing, data implies a role of adaptive immune response in islet dysfunction in T2D. Clinical trials validated anti-inflammatory therapies in T2D, while immune therapy for T1D remains challenging. Further research is required to improve our understanding of islet inflammatory pathways, and to identify more effective therapeutic targets for T1D and T2D.
β cell; adipocyte; cytokine; immune cells; obesity; clinical trials
The absorptive epithelium of the proximal small intestine converts oleic acid released during fat digestion into oleoylethanolamide (OEA), an endogenous high-affinity agonist of peroxisome proliferator-activated receptor-α (PPAR-α). OEA interacts with this receptor to cause a state of satiety characterized by prolonged inter-meal intervals and reduced feeding frequency. The two main branches of the autonomic nervous system, sympathetic and parasympathetic, contribute to this effect: the former by enabling OEA mobilization in the gut and the latter by relaying the OEA signal to brain structures, such as the hypothalamus, that are involved in feeding regulation. OEA signaling may be a key component of the physiological system devoted to the monitoring of dietary fat intake, and its dysfunction might contribute to overweight and obesity.
Type 1 diabetes mellitus (T1DM) is a chronic disease resulting from destruction of insulin-producing pancreatic β cells. Genetic and environmental factors contribute to T1DM onset. Use of high-throughput DNA sequencing has allowed geneticists to perform genome-wide association studies (GWAS) to identify novel gene loci associated with T1DM. Interestingly, >50% of these genes encode products that are expressed in β cells. These studies, coupled with emerging molecular evidence that β cells are impaired by gain-of-function or loss-of-function of these loci, suggest an active role for the β cell in eliciting its own demise. Although immune dysregulation plays a vital role in T1DM pathogenesis, understanding the mechanisms contributing to β cell failure may lead to new strategies to preserve or improve β cell function in patients with T1DM.
T1DM; islet; GWAS; insulin
The establishment of the male internal reproductive system involves two crucial events: the formation of the testis and the maintenance and differentiation of the Wolffian duct. Testis formation, particularly the specification of Sertoli cell and Leydig cell lineages, is controlled strictly by genetic components initiated by the testis-determining gene SRY (sex-determining region of the Y chromosome). Conversely, Wolffian duct differentiation is not directly mediated via the composition of the sex chromosome or SRY; instead, it relies on androgens derived from the Leydig cells. Leydig cells do not express SRY, indicating that a crosstalk must be present between the SRY-positive Sertoli and Leydig cells to ensure normal androgen production. Recent advancement of genetic and genomic approaches has unveiled the molecular pathways for differentiation of Sertoli cells and Leydig cells as well as development of the Wolffian duct.
The uterine endometrium is exquisitely sensitive to steroid hormones that act through well-described nuclear receptors. Estrogen drives epithelial proliferation, and progesterone inhibits growth and causes cell differentiation. The importance of progesterone as a key inhibitor of carcinogenesis is reflected by the observation that women who ovulate and produce progesterone almost never get endometrial cancer. In this review we describe seminal research findings that define progesterone as the major endometrial tumor suppressor. We discuss the genes and diverse signaling pathways that are controlled by progesterone through progesterone receptors (PRs) and also the multiple factors that regulate progesterone/PR activity. By defining these progesterone-regulated factors and pathways we identify the principal therapeutic opportunities to control the growth of endometrial cancer.
Mammalian target of rapamycin (mTOR) has been implicated as a sensor of nutrient sufficiency for dividing cells and is activated by essential amino acids and glucose. However, cells also require lipids for membrane biosynthesis. A central metabolite in the synthesis of membrane phospholipids is phosphatidic acid (PA), which is required for the stability and activity of mTOR complexes. While PA is commonly generated by the phospholipase D-catalyzed hydrolysis of phosphatidylcholine, PA is also generated by diacylglycerol kinases and lysophosphatidic acid acyltransferases, which are at the center of phospholipid biosynthesis. It is proposed that the responsiveness of mTOR/TOR to PA evolved as a means for sensing lipid precursors for membrane biosynthesis prior to doubling the mass of a cell and dividing.
mTOR; phosphatidic acid; DG kinase; LPAAT; phospholipase D
Bone is a dynamic organ that undergoes continuous remodeling whilst maintaining a balance
between bone formation and resorption. Osteoblasts, which synthesize and mineralize new bone, and
osteoclasts, the cells that resorb bone, act in concert to maintain bone homeostasis. In recent
years, there has been increasing appreciation of purinergic regulation of bone metabolism.
Adenosine, released locally, mediates its physiologic and pharmacologic actions via interactions
with G-protein coupled receptors and recent work has indicated that these receptors are involved in
the regulation of osteoclast differentiation and function, as well as osteoblast differentiation and
bone formation. Moreover, adenosine receptors also regulate chondrocyte and cartilage homeostasis.
These recent findings underscore the potential therapeutic importance of adenosine receptors in
regulating bone physiology and pathology.
Adenosine; adenosine receptors; bone resorption; bone formation; chondrocytes
Skeletal muscle loss due to aging, motor neuron degeneration, cancer, heart failure and ischemia is a serious condition for which currently there is no effective treatment. Insulin-like growth factor 1 (IGF-I) plays an important role in muscle maintenance and repair. Preclinical studies have shown that IGF-I is involved in increasing muscle mass and strength, reducing degeneration, inhibiting the prolonged and excessive inflammatory process due to toxin injury and increasing the proliferation potential of satellite cells. However, clinical trials have not been successful due to ineffective delivery method. Choosing the appropriate isoforms or peptides and developing targeted delivery techniques can resolve this issue. Here we discuss the latest development in the field with special emphasis on novel therapeutic approaches.
muscle wasting; IGF-I; satellite cell
Nuclear, cytoplasmic and mitochondrial proteins are extensively modified by an O-linked β-N-acetylglucosamine (O-GlcNAc) moiety. This sugar modification regulates fundamental cellular processes in response to diverse nutritional and hormonal cues. The enzymes O-GlcNAc transferase (OGT) and O-linked β-N-acetylglucosaminase (O-GlcNAcase) mediate the addition and removal of O-GlcNAc, respectively. Aberrant O-GlcNAcylation has been implicated in a plethora of human diseases, including diabetes, cancer, aging, cardiovascular disease and neurodegenerative disease. As metabolic dysregulation is a vital component of these diseases, unraveling the roles of O-GlcNAc in metabolism is of emerging importance. Here, we review the current understanding of the functions of O-GlcNAc in cell signaling and gene transcription involved in metabolism, and focus on its relevance to diabetes, cancer, circadian rhythm, and mitochondrial function.
O-GlcNAc; hexosamine biosynthesis; insulin resistance; cancer metabolism; circadian rhythm; mitochondria
The circadian clock machinery orchestrates organism metabolism in order to ensure that development, survival and reproduction are attuned to diurnal environmental variations. For unknown reasons, there is a decline in circadian rhythms with age, concomitant with declines in the overall metabolic tissues homeostasis and changes in the feeding behavior of aged organisms. This disruption of the relationship between the clock and the nutrient sensing networks might underlie age-related diseases; overall, greater knowledge of the molecular mediators of and variations in clock networks during lifespan may shed light on the aging process and how it may be delayed. In this review we address the complex links between the circadian clock, metabolic (dys)functions and aging in different model organisms.
aging; circadian clock; glucose metabolism; insulin; flies; mice; nutrients
The decline in human muscle mass and strength (sarcopenia) is a hallmark of the aging process. A growing body of research in the areas of bioenergetics and protein turnover has placed the mitochondria at the center of this process. It is now clear that unless an active life style is rigorously followed, skeletal muscle mitochondrial decline occurs as humans’ age. Increasing research on mitochondrial biology has elucidated the regulatory pathways involved in mitochondrial biogenesis, many of which are potential therapeutic targets, and highlight the beneficial effects of vigorous physical activity on skeletal muscle health for an aging population.
sarcopenia; mitochondria; protein metabolism; protein synthesis; aging
Mitochondria have been largely considered as ‘end-function’ organelles, servicing the cell by producing energy and regulating cell death in response to complex signals. Being cellular entities with vital roles, mitochondria communicate back to the cell and actively engage in determining major cellular policies. These signals, collectively referred to as retrograde signals, are encoded in the nuclear genome, or are secondary products of mitochondrial metabolism. Here, we discuss humanin, the first small peptide of a putative set of mitochondrial-derived peptides, which exhibits strong cytoprotective actions against various stress and disease models. The study of humanin and other mitochondrial-derived retrograde signal peptides will aid in the identification of genes and peptides with therapeutic and diagnostic potential in treating human diseases.
Humanin; mitochondria; retrograde signaling; protection; stress-resistance; mitochondrial-derived peptide
Insulin controls nutrient and metabolic homeostasis via the IRS–PI3K–AKT signaling cascade that targets FOXO1 and mTOR. Mitochondria, as the prime metabolic platform, malfunction during insulin resistance in metabolic diseases. However, the molecular link between insulin resistance and mitochondrial dysfunction remains undefined. Here we review recent studies on insulin action and the mechanistic association with mitochondrial metabolism. These studies suggest that insulin signaling underpins mitochondrial electron transport chain integrity and activity by suppressing FOXO1/HMOX1 and maintaining the NAD+/NADH ratio, the mediator of the SIRT1/PGC1α pathway for mitochondrial biogenesis and function. Mitochondria generate moderately reactive oxygen species (ROS) and enhance insulin sensitivity upon redox regulation of protein tyrosine phosphatase and insulin receptor. However, chronic exposure to high ROS levels could alter mitochondrial function and thereby cause insulin resistance.
Brown adipose tissue (BAT) is specialized for heat generation and energy expenditure as a defense against cold and obesity; in both humans and mice increased amounts of BAT are associated with a lean phenotype and resistance to development of the metabolic syndrome and its complications. Here we summarize recent research showing that several BAT-expressed microRNAs miRNAs) play important roles in regulating differentiation and metabolism of brown and beige adipocytes; we discuss the key mRNA targets downregulated by these miRNAs and show how these miRNAs affect directly or indirectly transcription factors important for BAT development. We suggest that these miRNAs could be part of novel therapeutics to increase BAT in humans.
Brown; beige adipocytes; microRNAs; BAT; adipogenesis
Highly proliferative cells, including cancer cells, require a constant supply of molecular building blocks to support their growth. To acquire substrates such as glucose and amino acids from the extracellular space, dividing cells rely on transporter proteins in the plasma membrane. Numerous studies link transcriptional and post-translational control of nutrient transporter expression with proliferation, highlighting the importance of nutrient transporters in both physiologic and pathologic growth. Here we review recent work that spotlights the crucial role of nutrient transporters in cell growth and proliferation, discuss post-translational mechanisms for coordinating expression of different transporters, and consider the therapeutic potential of targeting these proteins in cancer and other diseases characterized by inappropriate cell division.
nutrient transporters; proliferation; cancer; growth; glucose; amino acids
Guanylyl cyclase C (GUCY2C) has canonical centrality in defense of key intestinal homeostatic mechanisms, encompassing fluid and electrolyte balance, epithelial dynamics, antitumorigenesis, and intestinal barrier function. Recent discoveries expand the homeostatic role of GUCY2C to reveal a novel gut-brain endocrine axis regulating appetite, anchored by hypothalamic GUCY2C which is responsive to intestine-derived uroguanylin. Thus, GUCY2C may represent a new target for anti-obesity pharmacotherapy. Moreover, the coincident regulation of energy balance and tumor suppression by a single hormone receptor system suggests that the GUCY2C axis might contribute to the established relationship between obesity and colorectal cancer. This confluence suggests that hormone supplementation to reconstitute GUCY2C signaling may be an elegant strategy to reverse both pathophysiologic processes.
Guanylyl cyclase C (GUCY2C); uroguanylin; hypothalamus; obesity; colorectal cancer; pharmacotherapy
Monocytes and macrophages respond to and govern inflammation by producing a plethora of inflammatory modulators, including cytokines, chemokines and arachidonic acid (C20:4)-derived lipid mediators. One of the most prevalent inflammatory diseases is cardiovascular disease, caused by atherosclerosis, and accelerated by diabetes. Recent research has demonstrated that monocytes/macrophages from diabetic mice and humans with type 1 diabetes show upregulation of the enzyme, acyl-CoA synthetase 1 (ACSL1), which promotes C20:4 metabolism, and that ACSL1 inhibition selectively protects these cells from the inflammatory and pro-atherosclerotic effects of diabetes, in mice. Increased understanding of the role of ACSL1 and other culprits in monocytes/macrophages in inflammation and diabetes-accelerated atherosclerosis offers hope for new treatment strategies to combat diabetic vascular disease.
Acyl-CoA synthetase; Arachidonic acid; Eicosanoids; Macrophage; Monocyte
Glucocorticoids are essential for maintaining homeostasis and regulate a wide variety of physiological processes. Therapeutically, synthetic glucocorticoids are widely prescribed for the treatment of inflammation, autoimmune disorders, and malignancies of lymphoid origin. In this review we examine emerging evidence highlighting both proinflammatory and anti-inflammatory actions of glucocorticoids on both the innate and adaptive immune systems. We incorporate these findings into the more traditional anti-inflammatory role attributed to glucocorticoids, and propose how the two seemingly disparate processes seamlessly work together to resolve cellular responses to inflammatory stimuli. These ideas provide a framework by which glucocorticoids ready and reinforce the innate immune system, and repress the adaptive immune system, to help to resolve inflammation and restore homeostasis.
The superior efficacy of bariatric surgery compared with intensive medical treatment in reversing metabolic disease is now well accepted, but the critical mechanisms remain unknown. Unlike dieting, which triggers strong counter-regulatory responses such as hunger and craving, certain obesity surgeries appear to permanently reset the level of defended body weight. Understanding the molecular mechanisms behind successful surgery would thus go a long way in developing future “knifeless” treatment options. Major candidates include changes in gut-brain signaling by hormones, bile acids, and other still unidentified factors. By re-sensitizing homeostatic regulatory circuits in the hypothalamus and hedonic-motivational processing in cortico-limbic systems to internal signals, bariatric surgery could thus lead to a state of being content with less.
Obesity surgery; brain; Roux-en-Y gastric bypass surgery; hypothalamus; food reward
The central melanocortin system plays an essential role in the regulation of energy metabolism. Key to this regulation is the sensing and responses of neurons expressing proopiomelanocortin (POMC) and agouti-related protein (AgRP) to blood-borne metabolic signals. Recent evidence has demonstrated that POMC- and AgRP-neurons are not simply mirror opposites of each other in function and responsiveness to metabolic signals, nor are they exclusively first-order neurons. These neurons act as central transceivers, receiving both hormonal and neural signals, integrating and transmitting this information to peripheral tissues via the autonomic nervous system to coordinate whole body energy metabolism. This review focuses on most recent developments obtained from rodent studies on the function, metabolic regulation and circuitry of the central melanocortin system.
Agouti-related protein; proopiomelanocortin; melanocortin receptor; energy metabolism; feeding circuits; leptin; obesity
Glucagon-like peptide 1 (GLP-1) and GLP-1 analogs have received much recent attention due to the success of GLP-1 mimetics in treating type II diabetes mellitus (T2DM), but these compounds may also have the potential to treat obesity. The satiety effect of GLP-1 may involve both meal entero-enteric reflexes and across meal central signaling mechanisms to mediate changes in appetite and promote satiety. Here, we review the data supporting the role of both peripheral and central GLP-1signaling in the control of gastrointestinal motility and food intake. Understanding the mechanisms underlying the appetite suppressive effects of GLP-1 may help in developing targeted treatments for obesity.
GLP-1; appetite; gastrointestinal motility; food intake
Proopiomelanocortin (POMC)-expressing neurons in the hypothalamus integrate a variety of central and peripheral metabolic inputs, and regulate energy homeostasis by controlling energy expenditure and food intake. To accomplish this, a precise balance of production and degradation of α-melanocyte-stimulating hormone (α-MSH), an anorexigenic neuropeptide and product of the POMC gene, in the hypothalamus, is crucial. Prolyl carboxypeptidase (PRCP) is a key enzyme that degrades α-MSH to an inactive form unable to inhibit food intake. Because it represents a new therapeutic target for the treatment of metabolic disorders, such as obesity and diabetes, efforts have been made to generate potent, brain-penetrant PRCP inhibitors. Here, we discuss the role of PRCP on energy metabolism and the development of PRCP inhibitors.
hypothalamus; proopiomelanocortin; prolyl carboxypeptidase; enzymatic inhibitors; food intake