Recognition of the complex, multidimensional relationship between excess adiposity and cancer control outcomes has motivated the scientific community to seek new research models and paradigms.
The National Cancer Institute developed an innovative concept to establish a centers grant mechanism in nutrition, energetics, and physical activity; referred to as the Transdisciplinary Research on Energetics and Cancer (TREC) Initiative. This paper gives an overview of the 2011-2016 TREC Collaborative Network and the 15 research projects being conducted at the Centers.
Four academic institutions were awarded TREC center grants in 2011: Harvard University, University of California San Diego, University of Pennsylvania, and Washington University in St. Louis. The Fred Hutchinson Cancer Research Center is the Coordination Center. The TREC research portfolio includes 3 animal studies, 3 cohort studies, 4 randomized clinical trials, 1 cross-sectional study, and 2 modeling studies. Disciplines represented by TREC investigators include basic science, endocrinology, epidemiology, biostatistics, behavior, medicine, nutrition, physical activity, genetics, engineering, health economics, and computer science. Approximately 41,000 participants will be involved in these studies, including children, healthy adults, and breast and prostate cancer survivors. Outcomes include biomarkers of cancer risk, changes in weight and physical activity, persistent adverse treatment effects (e.g., lymphedema, urinary and sexual function), and breast and prostate cancer mortality.
The NIH Science of Team Science group will evaluate the value-added by this collaborative science. However, the most important outcome will be whether this transdisciplinary initiative improves the health of Americans at risk for cancer as well as cancer survivors.
energetics; obesity; diet; physical activity; cancer; transdisciplinary
The reduction of functional β cell mass is a key feature of type 2 diabetes. Here, we studied metabolic functions and islet gene expression profiles of C57BL/6J mice with naturally occurring nicotinamide nucleotide transhydrogenase (NNT) deletion mutation, a widely used model of diet-induced obesity and diabetes. On high fat diet (HF), the mice developed obesity and hyperinsulinemia, while blood glucose levels were only mildly elevated indicating a substantial capacity to compensate for insulin resistance. The basal serum insulin levels were elevated in HF mice, but insulin secretion in response to glucose load was significantly blunted. Hyperinsulinemia in HF fed mice was associated with an increase in islet mass and size along with higher BrdU incorporation to β cells. The temporal profiles of glucose-stimulated insulin secretion (GSIS) of isolated islets were comparable in HF and normal chow fed mice. Islets isolated from HF fed mice had elevated basal oxygen consumption per islet but failed to increase oxygen consumption further in response to glucose or carbonyl cyanide-4-trifluoromethoxyphenylhydrazone (FCCP). To obtain an unbiased assessment of metabolic pathways in islets, we performed microarray analysis comparing gene expression in islets from HF to normal chow-fed mice. A few genes, for example, those genes involved in the protection against oxidative stress (hypoxia upregulated protein 1) and Pgc1α were up-regulated in HF islets. In contrast, several genes in extracellular matrix and other pathways were suppressed in HF islets. These results indicate that islets from C57BL/6J mice with NNT deletion mutation develop structural, metabolic and gene expression features consistent with compensation and decompensation in response to HF diet.
Obesity is characterized by excess accumulation of lipids in adipose tissue and other organs, and chronic inflammation associated with insulin resistance and an increased risk of type 2 diabetes. Obesity, type 2 diabetes, and cardiovascular diseases are major health concerns. Resistin was first discovered as an adipose-secreted hormone (adipokine) linked to obesity and insulin resistance in rodents. Adipocyte-derived resistin is increased in obese rodents and strongly related to insulin resistance. However, in contrast to rodents, resistin is expressed and secreted from macrophages in humans and is increased in inflammatory conditions. Some studies have also suggested an association between increased resistin levels and insulin resistance, diabetes and cardiovascular disease. Genetic studies have provided additional evidence for a role of resistin in insulin resistance and inflammation. Resistin appears to mediate the pathogenesis of atherosclerosis by promoting endothelial dysfunction, vascular smooth muscle cell proliferation, arterial inflammation, and formation of foam cells. Indeed, resistin is predictive of atherosclerosis and poor clinical outcomes in patients with coronary artery disease and ischemic stroke. There is also growing evidence that elevated resistin is associated with the development of heart failure. This review will focus on the biology of resistin in rodents and humans, and evidence linking resistin with type 2 diabetes, atherosclerosis, and cardiovascular disease.
Adipocytes; Atherosclerosis; Cardiovascular diseases; Diabetes mellitus, type 2; Inflammation; Insulin resistance; Macrophages; Obesity; Polymorphism, genetic; Resistin
Globally, both the incidence of type 2 diabetes and the consumption of meat, in particular pork meat, have increased, concurrently. Processed meats have been associated with an increased risk for diabetes in observational studies. Therefore, it is important to understand the possible mechanisms of this association and the impact of meats from different species. The goal of this systematic review was to assess experimental human studies of the impact of pork intake compared with other protein sources on early markers for the development of diabetes, ie, insulin resistance, glucose intolerance, and the components of the metabolic syndrome. A systematic review was conducted searching PubMed and EMBASE and using the Cochrane and PRISMA guidelines. Eight studies were eligible and critically reviewed. Five studies were based on a single meal or single day exposure to pork, as compared with other sources of protein. The glucose-insulin response following the pork meals did not differ compared with beef, shrimp, or mixed sources of proteins. However, compared with eggs, ham (processed meat) led to a larger insulin response in nonobese subjects. Compared with whey, ham led to a smaller insulin response and a larger glucose response. These findings suggest possible mechanisms for the association between processed meat and the development of diabetes. Nonprocessed pork meats were not compared with eggs or whey. The three longer interventions (11 days to 6 months) did not show a significant impact of pork on the components of the metabolic syndrome, with the exception of a possible benefit on waist circumference and high-density lipoprotein cholesterol (one study each with significant limitations). Most of the findings are weak and there is a lack of solid evidence. The literature on the topic is limited and important research gaps are identified. Considering recent trends and projections for diabetes and pork intake, this is an important global public health question that requires more attention in order to provide improved evidence-based dietary recommendations.
blood glucose; high-density lipoprotein cholesterol; insulin resistance; meat; triglycerides; waist circumference
Night eating syndrome (NES) is characterized by evening hyperphagia and frequent awakenings accompanied by food intake. Patients with NES display a delayed circadian pattern of food intake but retain a normal sleep-wake cycle. These characteristics initiated the current study, in which the phase and amplitude of behavioral and neuroendocrine circadian rhythms in patients with NES were evaluated. Fifteen women with NES (mean age ± SD, 40.8 ± 8.7 y) and 14 control subjects (38.6 ± 9.5 y) were studied in the laboratory for 3 nights, with food intake measured daily. Blood also was collected for 25 h (every 2 h from 0800 to 2000 h, and then hourly from 2100 to 0900 h) and assayed for glucose and 7 hormones (insulin, ghrelin, leptin, melatonin, cortisol, thyroid-stimulating hormone [TSH] and prolactin). Statistical analyses utilized linear mixed-effects cosinor analysis. Control subjects displayed normal phases and amplitudes for all circadian rhythms. In contrast, patients with NES showed a phase delay in the timing of meals, and delayed circadian rhythms for total caloric, fat, and carbohydrate intake. In addition, phase delays of 1.0 to 2.8 h were found in 2 food-regulatory rhythms—leptin and insulin—and in the circadian melatonin rhythm (with a trend for a delay in the circadian cortisol rhythm). In contrast, circulating levels of ghrelin, the primary hormone that stimulates food intake, were phase advanced by 5.2 h. The glucose rhythm showed an inverted circadian pattern. Patients with NES also showed reduced amplitudes in the circadian rhythms of food intake, cortisol, ghrelin, and insulin, but increased TSH amplitude. Thus, patients with NES demonstrated significant changes in the timing and amplitude of various behavioral and physiological circadian markers involved in appetite and neuroendocrine regulation. As such, NES may result from dissociations between central (suprachiasmatic nucleus) timing mechanisms and putative oscillators elsewhere in the central nervous system or periphery, such as the stomach or liver. Considering these results, chronobiologic treatments for NES such as bright light therapy may be useful. Indeed, bright light therapy has shown efficacy in reducing night eating in case studies and should be evaluated in controlled clinical trials.
night eating syndrome; circadian rhythms; mixed-effects cosinor analysis; phase shifts; amplitude
The number of people who suffer from obesity and one or more of its adverse complications is rapidly increasing. It is becoming clear that diet, exercise, and other lifestyle modifications are insufficient strategies to combat this growing problem. Greater understanding of the mechanisms controlling our desire to feed and our ability to balance energy intake with energy expenditure are key to the development of pharmacological approaches for treating obesity. Although great strides have been made in our understanding of how the hypothalamus regulates feeding and energy balance, much less is known about how obesity affects the structure of the hypothalamus. The authors of two papers in this issue of the JCI have addressed this issue by examining the effects of obesity on neurons and glia in the hypothalamus. These studies reveal that obesity may be in part due to hypothalamic injury, which leads to inflammation and reduced neurogenesis. These findings support the notion that obesity is a disease that affects multiple organs, including the brain, and that disruption of normal brain function leads to abnormal regulation of peripheral metabolism.
Fatty liver disease is associated with obesity and type 2 diabetes, and hepatic lipid accumulation may contribute to insulin resistance by a variety of mechanisms. Here we show that mice with liver-specific deletion of histone deacetylase 3 (Hdac3) display severe hepatosteatosis and, notably increased insulin sensitivity without changes in insulin signaling or body weight. Hdac3 deletion reroutes metabolic precursors towards lipid synthesis and storage within lipid droplets (LDs). Reduced hepatic glucose production in Hdac3-depleted liver is a result of the metabolic rerouting rather than due to inherently defective gluconeogenesis. The lipid-sequestering LDs-coating protein Perilipin 2 is markedly induced upon Hdac3 deletion and contributes to the development of both steatosis and improved tolerance to glucose. These findings suggest that the sequestration of hepatic lipids ameliorates insulin resistance, and establish Hdac3 as a pivotal epigenomic modifier that integrate signals from the circadian clock in regulation of hepatic intermediary metabolism.
Considerable data support the idea that Foxo1 drives the liver transcriptional program during fasting and is inhibited by Akt after feeding. Mice with hepatic deletion of Akt1 and Akt2 were glucose intolerant, insulin resistant, and defective in the transcriptional response to feeding in liver. These defects were normalized upon concomitant liver–specific deletion of Foxo1. Surprisingly, in the absence of both Akt and Foxo1, mice adapted appropriately to both the fasted and fed state, and insulin suppressed hepatic glucose production normally. Gene expression analysis revealed that deletion of Akt in liver led to constitutive activation of Foxo1–dependent gene expression, but once again concomitant ablation of Foxo1 restored postprandial regulation, preventing its inhibition of the metabolic response to nutrient intake. These results are inconsistent with the canonical model of hepatic metabolism in which Akt is an obligate intermediate for insulin’s actions. Rather they demonstrate that a major role of hepatic Akt is to restrain Foxo1 activity, and in the absence of Foxo1, Akt is largely dispensable for hepatic metabolic regulation in vivo.
Leukocyte infiltration of adipose is a critical determinant of obesity-related metabolic diseases. Fractalkine (CX3CL1) and its receptor (CX3CR1) comprise a chemokine system involved in leukocyte recruitment and adhesion in atherosclerosis, but its role in adipose inflammation and type 2 diabetes is unknown.
RESEARCH DESIGN AND METHODS
CX3CL1 mRNA and protein were quantified in subcutaneous adipose and blood during experimental human endotoxemia and in lean and obese human adipose. CX3CL1 cellular source was probed in human adipocytes, monocytes, and macrophages, and CX3CL1-blocking antibodies were used to assess its role in monocyte-adipocyte adhesion. The association of genetic variation in CX3CR1 with metabolic traits was determined in a community-based sample. Finally, plasma CX3CL1 levels were measured in a case-control study of type 2 diabetes.
Endotoxemia induced adipose CX3CL1 mRNA (32.7-fold, P < 1 × 10−5) and protein (43-fold, P = 0.006). Obese subjects had higher CX3CL1 levels in subcutaneous adipose compared with lean (0.420 ± 0.387 vs. 0.228 ± 0.187 ng/mL, P = 0.04). CX3CL1 was expressed and secreted by human adipocytes and stromal vascular cells. Inflammatory cytokine induction of CX3CL1 in human adipocytes (27.5-fold mRNA and threefold protein) was completely attenuated by pretreatment with a peroxisome proliferator–activated receptor-γ agonist. A putative functional nonsynonymous single nucleotide polymorphism (rs3732378) in CX3CR1 was associated with adipose and metabolic traits, and plasma CX3CL1 levels were increased in patients with type 2 diabetes vs. nondiabetics (0.506 ± 0.262 vs. 0.422 ± 0.210 ng/mL, P < 0.0001).
CX3CL1-CX3CR1 is a novel inflammatory adipose chemokine system that modulates monocyte adhesion to adipocytes and is associated with obesity, insulin resistance, and type 2 diabetes. These data provide support for CX3CL1 as a diagnostic and therapeutic target in cardiometabolic disease.
Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the lifespans of yeast, flies, and mice. Calorie restriction, which increases lifespan and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapamycin substantially impairs glucose tolerance and insulin action. We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis. Further, decreased mTORC1 signaling was sufficient to extend lifespan independently from changes in glucose homeostasis, as female mice heterozygous for both mTOR and mLST8 exhibited decreased mTORC1 activity and extended lifespan, but had normal glucose tolerance and insulin sensitivity. Thus, mTORC2 disruption is an important mediator of the effects of rapamycin in vivo.
Metabolic syndrome has deleterious effects on the central nervous system, and recent evidence suggests that obesity rates are higher at presentation in children who develop epilepsy. Adiponectin is secreted by adipose tissue and acts in the brain and peripheral organs to regulate glucose and lipid metabolism. Adiponectin deficiency predisposes toward metabolic syndrome, characterized by obesity, insulin resistance, impaired glucose tolerance, hyperlipidemia, and cardiovascular morbidity. To investigate the relationship between metabolic syndrome and seizures, wild type C57BL/6J and adiponectin knockout mice were fed a high-fat diet, followed by treatment with low doses of kainic acid to induce seizures. Adiponectin deficiency in mice fed a high-fat diet resulted in greater fat accumulation, impaired glucose tolerance, hyperlipidemia, increased seizure severity and increased hippocampal pathology. In contrast, there were no adverse effects of adiponectin deficiency on metabolic phenotype or seizure activity in mice fed a normal (low fat) chow diet. These findings demonstrate that metabolic syndrome modulates the outcome of seizures and brain injury.
metabolic syndrome; hormone; metabolism; epilepsy; gliosis
Although adipocyte-derived murine resistin links insulin resistance to obesity, the role of human resistin, predominantly expressed in mononuclear cells and induced by inflammatory signals, remains unclear. Given the mounting evidence that obesity and type 2 diabetes are inflammatory diseases, we sought to determine the relationship between inflammatory increases in human resistin and insulin resistance.
RESEARCH DESIGN AND METHODS
To investigate the role of human resistin on glucose homeostasis in inflammatory states, we generated mice lacking murine resistin but transgenic for a bacterial artificial chromosome containing human resistin (BAC-Retn), whose expression was similar to that in humans. The metabolic and molecular phenotypes of BAC-Retn mice were assessed after acute and chronic endotoxemia (i.e., exposure to inflammatory lipopolysaccharide).
We found that BAC-Retn mice have circulating resistin levels within the normal human range, and similar to humans, lipopolysaccharide markedly increased serum resistin levels. Acute endotoxemia caused hypoglycemia in mice lacking murine resistin, and this was attenuated in BAC-Retn mice. In addition, BAC-Retn mice developed severe hepatic insulin resistance under chronic endotoxemia, accompanied by increased inflammatory responses in liver and skeletal muscle.
These results strongly support the role of human resistin in the development of insulin resistance in inflammation. Thus, human resistin may link insulin resistance to inflammatory diseases such as obesity, type 2 diabetes, and atherosclerosis.
Major depressive disorder (MDD) is associated with immune system dysfunction and disruption of multiple circadian systems. Adiponectin is an adipocytokine with anti-inflammatory and anti-atherogenic effects. Circulating concentrations are inversely related to adiposity and risks of metabolic syndrome and diabetes mellitus. Our goals were to: A) establish whether premenopausal women with MDD exhibit decreased plasma adiponectin concentrations and/or disruption of circadian adiponectin rhythmicity; B) assess whether there is a relationship between adiponectin and MDD; C) explore the temporal relationships among adiponectin, leptin, ACTH and cortisol secretion.
Case-control study of community-dwelling premenopausal women with MDD and age- and BMI-matched-control subjects (N=23/group). Main outcome measures were circulating concentrations of adiponectin, leptin, ACTH, and cortisol measured hourly for 24h.
Women with MDD had approximately 30% lower mean 24h concentrations of adiponectin than did control subjects. Adiponectin was inversely related to depression severity and total duration of disease, suggesting a causal link. In contrast, nocturnal leptin concentrations were higher in the MDD versus control groups. Leptin was inversely related to cortisol and adiponectin both in subjects with depression and in control subjects. In cross-correlation analyses, the relationship between ACTH and cortisol was stronger in women with MDD than in control subjects, consistent with HPA-axis activation in MDD.
Reduced daily adiponectin production may increase the risk of diabetes mellitus, and elevated leptin may contribute to osteoporosis, in premenopausal women with MDD.
women’s health; psychosomatic medicine; antidepressants; stress system; circadian rhythmicity; inflammation; adipocytokines: ACTH; cortisol: insulin resistance, cardiovascular risk; osteoporosis; osteopenia
Leptin exerts a permissive action on puberty by stimulating release of gonadotropin-releasing hormone (GnRH) in the hypothalamus. However, GnRH neurons lack leptin receptor (LepR), indicating that leptin must indirectly regulate these neurons. The Kiss1 gene produces kisspeptins that stimulate GnRH secretion. Because Kiss1 neurons express LepR and inactivation of Kiss1 causes hypogonadotropic hypogonadism, Donato et al., in this issue of the JCI, assessed whether deletion of LepR from Kiss1 neurons would prevent sexual maturation. Unexpectedly, mice lacking LepR in Kiss1 neurons had normal pubertal development and fertility. In contrast, deletion of LepR from the ventral premammillary nucleus, a region of the brain involved in sexual behavior, prevented puberty and fertility. These findings highlight the complex biology of leptin in reproduction.
The growing problem of obesity is associated with multiple morbidities, including increased risk of diabetes, hypertension, heart disease, sleep apnea, and cancer. Obesity promotes disability, decreases productivity, and shortens life span. Although much attention has been focused on diet and exercise, these strategies alone are not effective in preventing obesity and maintaining weight loss. Moreover, the development of pharmacological approaches for obesity treatment has been dogged by poor efficacy and serious side effects. The biology of obesity is very complex, and mechanisms linking obesity to various diseases are poorly understood. This issue of the JCI highlights important concepts in our understanding of the pathogenesis of obesity and its complications.
In a prior study, we have shown that tumor necrosis factor (TNF)-α neutralization improves inflammatory markers and total adiponectin in patients with the metabolic syndrome, without improving insulin sensitivity. In this study, we sought to extend our understanding of the effects of TNF-α neutralization in this human model of obesity by investigating the responses of high-molecular-weight (HMW) adiponectin, resistin, leptin, and muscle adiposity to etanercept in patients with the metabolic syndrome. Fifty-six men and women with the metabolic syndrome enrolled in a double-blind randomized placebo-controlled trial. Circulating concentrations of total and HMW adiponectin, resistin, and leptin were determined at baseline and after 4 wk of treatment with etanercept. Muscle adiposity was measured by computed tomography (CT). Although etanercept increased total adiponectin concentration, the HMW form, which is thought to mediate insulin sensitivity, was unchanged. Thus the ratio of HMW to total adiponectin decreased following etanercept treatment compared with placebo (−0.03 ± 0.03 vs. 0.06 ± 0.03, P = 0.02). Resistin tended to decrease in the etanercept-treated group compared with placebo (−0.6 ± 0.7 vs. 1.2 ± 0.7 ng/ml, P = 0.06), whereas leptin was not altered. Etanercept decreased muscle attenuation on CT [−0.61 ± 0.64 Hounsfield units (HU) vs. 1.54 ± 0.77 HU in placebo, P = 0.04], suggesting an increase in muscle adiposity. Together, these results demonstrate that neutralization of TNF-α in obese humans results in differential effects on critical adipokines and body composition indexes. These findings may help to explain the lack of effect on insulin sensitivity and extend our knowledge of the biological effects of TNF-α neutralization in obesity.
tumor necrosis factor-α; adiponectin; resistin; muscle adiposity; metabolic syndrome
IL-15 receptor α (IL-15Rα) is a component of the heterotrimeric plasma membrane receptor for the pleiotropic cytokine IL-15. However, IL-15Rα is not merely an IL-15 receptor subunit, as mice lacking either IL-15 or IL-15Rα have unique phenotypes. IL-15 and IL-15Rα have been implicated in muscle phenotypes, but a role in muscle physiology has not been defined. Here, we have shown that loss of IL-15Rα induces a functional oxidative shift in fast muscles, substantially increasing fatigue resistance and exercise capacity. IL-15Rα–knockout (IL-15Rα–KO) mice ran greater distances and had greater ambulatory activity than controls. Fast muscles displayed fatigue resistance and a slower contractile phenotype. The molecular signature of these muscles included altered markers of mitochondrial biogenesis and calcium homeostasis. Morphologically, fast muscles had a greater number of muscle fibers, smaller fiber areas, and a greater ratio of nuclei to fiber area. The alterations of physiological properties and increased resistance to fatigue in fast muscles are consistent with a shift toward a slower, more oxidative phenotype. Consistent with a conserved functional role in humans, a genetic association was found between a SNP in the IL15RA gene and endurance in athletes stratified by sport. Therefore, we propose that IL-15Rα has a role in defining the phenotype of fast skeletal muscles in vivo.
The adipocyte-derived hormone adiponectin signals from the fat storage depot to regulate metabolism in peripheral tissues. Inversely correlated with body fat levels, adiponectin reduction in obese individuals may play a causal role in the symptoms of metabolic syndrome. Adiponectin lowers serum glucose through suppression of hepatic glucose production, an effect attributed to activation of AMPK. Here, we investigated the signaling pathways that mediate the effects of adiponectin by studying mice with inducible hepatic deletion of LKB1, an upstream regulator of AMPK. We found that loss of LKB1 in the liver partially impaired the ability of adiponectin to lower serum glucose, though other actions of the hormone were preserved, including reduction of gluconeogenic gene expression and hepatic glucose production as assessed by euglycemic hyperinsulinemic clamp. Furthermore, in primary mouse hepatocytes, the absence of LKB1, AMPK, or the transcriptional coactivator CRTC2 did not prevent adiponectin from inhibiting glucose output or reducing gluconeogenic gene expression. These results reveal that whereas some of the hormone’s actions in vivo may be LKB1 dependent, substantial LKB1-, AMPK-, and CRTC2-independent signaling pathways also mediate effects of adiponectin.
The composition of the gut microbiome is affected by host phenotype, genotype, immune function, and diet. Here we used the phenotype of RELMβ Knockout (KO) mice to assess the influence of these factors.
Methods and Results
Both wild-type and RELMβ KO mice were lean on a standard chow diet, but upon switching to a high fat diet, wild-type mice became obese while RELMβ KO mice remained comparatively lean. To investigate the influence of diet, genotype, and obesity on microbiome composition we used deep sequencing to characterize 25,790 16S rDNA sequences from uncultured bacterial communities from both genotypes on both diets. We found large alterations associated with switching to the high fat diet, including a decrease in Bacteroidetes and an increase in both Firmicutes and Proteobacteria. This was seen for both genotypes (i.e. in the presence and absence of obesity), indicating that the high fat diet itself, and not the obese state, mainly accounted for the observed changes in the gut microbiota. The RELMβ genotype also modestly influenced microbiome composition independently of diet. Metagenomic analysis of 537,604 sequence reads documented extensive changes in gene content due to a high fat diet, including an increase in transporters and two-component sensor-responders as well as a general decrease in metabolic genes. Unexpectedly, we found a substantial amount of murine DNA in our samples that increased in proportion on a high fat diet.
These results demonstrate the importance of diet as a determinant of gut microbiome composition and suggest the need to control for dietary variation when evaluating the composition of the human gut microbiome.
Akt is a critical mediator of developmental skeletal muscle growth. Treatment with a soluble ActRIIB fusion protein (ActRIIB-mFc) increases skeletal muscle mass and strength by inhibiting myostatin and related peptides. Recent in vitro studies have suggested that Akt signaling is necessary for the ability of ActRIIB inhibition to induce muscle hypertrophy. Thus, we hypothesized that mice deficient in either Akt1 or Akt2 would not respond to in vivo inhibition of ActRIIB with ActRIIB-mFc treatment.
Methodology and Principal Findings
We analyzed body composition and muscle parameters in wild-type C57BL/6J and Akt1 and Akt2 knockout mice, and compared the responses to blockade of ActRIIB signaling via ActRIIB-mFc treatment. Mice lacking Akt1 or Akt2 had reduced muscle mass, grip strength and contractile force. However, deficiency of Akt1 or Akt2 did not prevent the ability of ActRIIB-mFc treatment to induce muscle hypertrophy, or increase grip strength and contractile force. Akt1 and Akt2 deficient mice responded similarly as wild type mice to ActRIIB-mFc treatment by increasing fiber size.
Conclusions and Significance
Akt1 and Akt2 are important for the regulation of skeletal muscle mass and function. However, these Akt isoforms are not essential for the ability of ActRIIB inhibition to regulate muscle size, fiber type, strength or contractile force.
The liver contributes to glucose homeostasis by promoting either storage or production of glucose depending on the physiological state. The cAMP response element binding protein (CREB) is a principal regulator of genes involved in coordinating the hepatic response to fasting, but its mechanism of gene activation remains controversial. We derived CRTC2-(CREB-regulated transcription coactivator 2; previously TORC2) deficient mice to assess the contribution of this cofactor to hepatic glucose metabolism in vivo. CRTC2 mutant hepatocytes showed reduced glucose production in response to glucagon, which correlated with decreased CREB binding to several gluconeogenic genes. However, despite attenuated expression of CREB target genes including PEPCK, G6Pase, and PGC1α, no hypoglycemia was observed in mutant mice. Collectively, these results provide genetic evidence supporting a role for CRTC2 in the transcriptional response to fasting, but indicate only a limited contribution of this cofactor to the maintenance of glucose homeostasis.
Myostatin, also known as Growth and Differentiation Factor 8, is a secreted protein that inhibits muscle growth. Disruption of myostatin signaling increases muscle mass and decreases glucose, but it is unclear whether these changes are related. We treated mice on chow and high-fat diets with a soluble activin receptor type IIB (ActRIIB.Fc) which is a putative endogenous signaling receptor for myostatin and other ligands of the TGF-β superfamily. After 4 weeks, RAP-031 increased lean and muscle mass, grip strength, and contractile force. RAP-031 enhanced the ability of insulin to suppress glucose production under clamp conditions in high-fat fed mice, but did not significantly change insulin-mediated glucose disposal. The hepatic insulin sensitizing effect of RAP-031 treatment was associated with increased adiponectin levels. RAP-031 treatment for 10 weeks further increased muscle mass and drastically reduced fat content in mice on either chow or high-fat diet. RAP-031 suppressed hepatic glucose production and increased peripheral glucose uptake in chow fed mice. In contrast, RAP-031 suppressed glucose production with no apparent change in glucose disposal in high-fat diet mice. Our findings demonstrate that disruption of ActRIIB signaling is a viable pharmacological approach for treating obesity and diabetes.
activin receptor; myostatin; muscle; insulin; glucose; mice
Interest in the control feeding and has increased as a result of the obesity epidemic and rising incidence of metabolic diseases. The brain detects alterations in energy stores and triggers metabolic and behavioral responses designed to maintain energy balance. Energy homeostasis is controlled mainly by neuronal circuits in the hypothalamus and brainstem, whereas reward and motivation aspects of eating behavior are controlled by neurons in limbic regions and cerebral cortex. This article provides an integrated perspective on how metabolic signals emanating from the gastrointestinal tract, adipose tissue and other peripheral organs target the brain to regulate feeding, energy expenditure and hormones. Knowledge of these complex pathways is crucial to the pathogenesis and treatment of obesity and abnormalities of glucose and lipid metabolism.
Nervous system; appetite; metabolism; adipokine; neuropeptide
Rhythmic changes in histone acetylation at circadian clock genes suggest that temporal modulation of gene expression is regulated by chromatin modifications1–3. Furthermore, recent studies demonstrate a critical relationship between circadian and metabolic physiology4–7. The Nuclear Receptor Co-Repressor 1 (NCoR) functions as an activating subunit for the chromatin modifying enzyme histone deacetylase 3 (HDAC3)8. Lack of NCoR is incompatible with life, and hence it is unknown whether NCoR, and particularly its regulation of HDAC3, is critical for adult mammalian physiology9. Here we show that specific, genetic disruption of the NCoR-HDAC3 interaction in mice causes aberrant regulation of clock genes and results in abnormal circadian behavior. These mice are also leaner and more insulin sensitive due to increased energy expenditure. Unexpectedly, loss of a functional NCoR-HDAC3 complex in vivo does not lead to sustained elevations of known catabolic genes, but rather significantly alters the oscillatory patterns of several metabolic genes, demonstrating that circadian regulation of metabolism is critical for normal energy balance. These findings indicate that activation of HDAC3 by NCoR is a nodal point in the epigenetic regulation of circadian and metabolic physiology.