The role of bone in energy metabolism: A focus on osteocalcin.

Understanding the mechanisms involved in whole body glucose regulation is key for the discovery of new treatments for type 2 diabetes (T2D). Historically, glucose regulation was largely focused on responses to insulin and glucagon. Impacts of incretin-based therapies, and importance of muscle mass, are also highly relevant.

Undercarboxylated osteocalcin and ibandronate combination ameliorates hindlimb immobilization-induced muscle wasting.

Immobilization leads to muscle wasting and insulin resistance, particularly during ageing. It has been suggested that undercarboxylated osteocalcin (ucOC) improves muscle mass and glucose metabolism. Bisphosphonates, an anti-osteoporosis treatment, might protect muscle wasting independent of ucOC.

The Effects of Acute High-Intensity Interval Exercise and Hyperinsulinemic-Euglycemic Clamp on Osteoglycin Levels in Young and Middle-Aged Men.

Osteoglycin (OGN) is a leucine-rich proteoglycan that has been implicated in the regulation of glucose in animal models. However, its relationship with glucose control in humans is unclear. We examined the effect of high-intensity interval exercise (HIIE) and hyperinsulinemic-euglycemic clamp on circulating levels of OGN as well as whether circulating OGN levels are associated with markers of glycemic control and cardio-metabolic health.

Higher bone remodeling biomarkers are related to a higher muscle function in older adults: Effects of acute exercise.

Bone and muscle are closely linked mechanically and biochemically. Bone hormones secreted during bone remodeling might be linked to muscle mass and strength maintenance. Exercise elicits high mechanical strain and is essential for bone health.

Defective AMPK regulation of cholesterol metabolism accelerates atherosclerosis by promoting HSPC mobilization and myelopoiesis.

Objectives: Dysregulation of cholesterol metabolism in the liver and hematopoietic stem and progenitor cells (HSPCs) promotes atherosclerosis development. Previously, it has been shown that HMG-CoA-Reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway, can be phosphorylated and inactivated by the metabolic stress sensor AMP-activated protein kinase (AMPK). However, the physiological significance of AMPK regulation of HMGCR to atherogenesis has yet to be elucidated.

Neuropeptide Y1 receptor antagonism protects β-cells and improves glycemic control in type 2 diabetes.

Objectives: Loss of functional β-cell mass is a key factor contributing to poor glycemic control in advanced type 2 diabetes (T2D). We have previously reported that the inhibition of the neuropeptide Y1 receptor improves the islet transplantation outcome in type 1 diabetes (T1D). The aim of this study was to identify the pathophysiological role of the neuropeptide Y (NPY) system in human T2D and further evaluate the therapeutic potential of using the Y1 receptor antagonist BIBO3304 to improve β-cell function and survival in T2D.

Osteoglycin Across the Adult Lifespan.

Context: Osteoglycin (OGN) is a proteoglycan released from bone and muscle which has been associated with markers of metabolic health. However, it is not clear whether the levels of circulating OGN change throughout the adult lifespan or if they are associated with clinical metabolic markers or fitness.

Objective: We aimed to identify the levels of circulating OGN across the lifespan and to further explore the relationship between OGN and aerobic capacity as well as OGN's association with glucose and HOMA-IR.

Uncovering the Bone-Muscle Interaction and Its Implications for the Health and Function of Older Adults (the Wellderly Project): Protocol for a Randomized Controlled Crossover Trial.

Background: Bone and muscle are closely linked anatomically, biochemically, and metabolically. Acute exercise affects both bone and muscle, implying a crosstalk between the two systems. However, how these two systems communicate is still largely unknown.

The effects of acute exercise on bone turnover markers in middle-aged and older adults: A systematic review.

Background: Bone turnover is the cellular machinery responsible for bone integrity and strength and, in the clinical setting, it is assessed using bone turnover markers (BTMs). Acute exercise can induce mechanical stress on bone which is needed for bone remodelling, but to date, there are conflicting results in regards to the effects of varying mechanical stimuli on BTMs.

Objectives: This systematic review examines the effects of acute aerobic, resistance and impact exercises on BTMs in middle and older-aged adults and examines whether the responses are determined by the exercise mode, intensity, age and sex.

Roles of bone-derived hormones in type 2 diabetes and cardiovascular pathophysiology.

Background: Emerging evidence demonstrates that bone is an endocrine organ capable of influencing multiple physiological and pathological processes through the secretion of hormones. Recent research suggests complex crosstalk between the bone and other metabolic and cardiovascular tissues. It was uncovered that three of these bone-derived hormones-osteocalcin, lipocalin 2, and sclerostin-are involved in the endocrine regulations of cardiometabolic health and play vital roles in the pathophysiological process of developing cardiometabolic syndromes such as type 2 diabetes and cardiovascular disease.

Undercarboxylated Osteocalcin Improves Insulin-Stimulated Glucose Uptake in Muscles of Corticosterone-Treated Mice.

Short-term administration of glucocorticoids (GCs) impairs muscle insulin sensitivity at least in part via the reduction of undercarboxylated osteocalcin (ucOC). However, whether ucOC treatment reverses the GC-induced muscle insulin resistance remains unclear. To test the hypothesis that ucOC directly ameliorates impaired insulin-stimulated glucose uptake (ISGU) induced by short-term GC administration in mice muscle and to identify the molecular mechanisms, mice were implanted with placebo or corticosterone (CS) slow-release pellets.

Normal increases in insulin-stimulated glucose uptake after ex vivo contraction in neuronal nitric oxide synthase mu (nNOSμ) knockout mice.

Nitric oxide (NO) is involved in skeletal muscle glucose uptake during exercise and also in the increase in insulin sensitivity after exercise. Given that neuronal nitric oxide synthase (NOS) isoform mu (nNOSμ) is a major isoform of NOS in skeletal muscle, we examined if the increase in skeletal muscle insulin-stimulated glucose uptake 3.5 h following ex vivo contraction of extensor digitorum longus (EDL) is reduced in muscles from nNOSμ and nNOSμ mice compared with nNOSμ mice.

Glucocorticoid-Induced Insulin Resistance in Men Is Associated With Suppressed Undercarboxylated Osteocalcin.

In mice, glucocorticoid-induced insulin resistance occurs largely through impaired osteoblast function and decreased circulating undercarboxylated osteocalcin (ucOC). Whether these mechanisms contribute to glucocorticoid-induced insulin resistance in humans has yet to be established. In addition, the effects of glucocorticoids on the exercise-induced increase in circulating ucOC and insulin sensitivity are also unknown.

Undercarboxylated Osteocalcin: Experimental and Human Evidence for a Role in Glucose Homeostasis and Muscle Regulation of Insulin Sensitivity.

Recent advances have indicated that osteocalcin, and in particular its undercarboxylated form (ucOC), is not only a nutritional biomarker reflective of vitamin K status and an indicator of bone health but also an active hormone that mediates glucose metabolism in experimental studies. This work has been supported by the putative identification of G protein-coupled receptor, class C, group 6, member A (GPRC6A) as a cell surface receptor for ucOC. Of note, ucOC has been associated with diabetes and with cardiovascular risk in epidemiological studies, consistent with a pathophysiological role for ucOC in vivo.

Uncarboxylated Osteocalcin Enhances Glucose Uptake Ex Vivo in Insulin-Stimulated Mouse Oxidative But Not Glycolytic Muscle.

Uncarboxylated osteocalcin (ucOC) stimulates muscle glucose uptake in mice EDL and soleus muscles. However, whether ucOC also exerts a similar effect in insulin-stimulated muscles in a muscle type-specific manner is currently unclear. We aimed to test the hypothesis that, with insulin stimulation, ucOC per se has a greater effect on oxidative muscle compared with glycolytic muscle, and to explore the underlying mechanisms.

Recombinant Uncarboxylated Osteocalcin Enhances Mouse Skeletal Muscle Glucose Uptake in both Extensor Digitorum Longus and Soleus Muscles.

Emerging evidence suggests that undercarboxylated osteocalcin (ucOC) improves muscle glucose uptake in rodents. However, whether ucOC can directly increase glucose uptake in both glycolytic and oxidative muscles and the possible mechanisms of action still need further exploration. We tested the hypothesis that ucOC stimulates muscle glucose uptake extracellular signal-regulated kinase (ERK), adenosine monophosphate-activated protein kinase (AMPK), and/or the mechanistic target of rapamycin complex 2 (mTORC2)-protein kinase B (AKT)-AKT substrate of 160 kDa (AS160) signaling cascade.

Hindlimb Immobilization, But Not Castration, Induces Reduction of Undercarboxylated Osteocalcin Associated With Muscle Atrophy in Rats.

Undercarboxylated osteocalcin (ucOC) has been implicated in skeletal muscle insulin sensitivity and function. However, whether muscle mass and strength loss in atrophic conditions is related to a reduction in ucOC is not clear. We hypothesized that both immobilization and testosterone depletion would lead to reductions in ucOC, associated with not only the degree of muscle atrophy but also changes to atrophy signaling pathway(s) in male rats.

Oxidative stress in malignant melanoma enhances tumor necrosis factor-α secretion of tumor-associated macrophages that promote cancer cell invasion.

Aims: Malignant melanoma is well known for abundant reactive oxygen species (ROS) that exist in the primary tumor environment. Within this microenvironment, tumor-associated macrophages (TAMs) play substantial roles in multiple steps of tumor development in terms of tumor growth, invasion, and metastasis. We therefore aimed to determine whether this high-level ROS in primary melanoma is capable to promote tumor invasiveness by influencing TAM properties.

Cell-death-mode switch from necrosis to apoptosis in hydrogen peroxide treated macrophages.

Cell death is typically defined either as apoptosis or necrosis. Because the consequences of apoptosis and necrosis are quite different for an entire organism, the investigation of the cell-death-mode switch has considerable clinical significance. The existence of a necrosis-to-apoptosis switch induced by hydrogen peroxide in macrophage cell line RAW 264.

Evaluating bistability of Bax activation switch.

Mitochondrial apoptotic pathway is precisely controlled by BCL-2 family. Complex interactions of BCL-2 family proteins constitute a bistable switch of which detailed experimental and theoretical delineation remains elusive. In this paper, combined approaches were used to explore the bistability of Bax activation switch.

Redox imbalance provokes deactivation of macrophages in sepsis.

Sepsis accounts for the majority of deaths in critically ill patients. Symptoms of septic disease are often associated with monocyte/macrophage desensitization. In the current study, impaired macrophage function was determined in a sepsis mouse model with decreased cytokine release and weak phagocytosis, coinciding with ectopic elevation of serum-ROS levels.