The role of tissue oxygenation in obesity-related cardiometabolic complications.

Obesity is a complex, multifactorial, chronic disease that acts as a gateway to a range of other diseases. Evidence from recent studies suggests that changes in oxygen availability in the microenvironment of metabolic organs may exert an important role in the development of obesity-related cardiometabolic complications. In this review, we will first discuss results from observational and controlled laboratory studies that examined the relationship between reduced oxygen availability and obesity-related metabolic derangements.

Effects of Early and Late Time-Restricted Feeding on Parameters of Metabolic Health: An Explorative Literature Assessment.

Chrono-nutrition (meal timing) aligns food consumption with one's circadian rhythm. The first meal (e.g.

Fetuin B in white adipose tissue induces inflammation and is associated with peripheral insulin resistance in mice and humans.

Objective: Fetuin B is a steatosis-responsive hepatokine that causes glucose intolerance in mice, but the underlying mechanisms remain incompletely described. This study aimed to elucidate the mechanisms of action of fetuin B by investigating its putative effects on white adipose tissue metabolism.

Methods: First, fetuin B gene and protein expression was measured in multiple organs in mice and in cultured adipocytes.

Nutritional strategies to attenuate postprandial glycemic response.

Maintaining good glycemic control to prevent complications is crucial in people with type 2 diabetes and in people with prediabetes and in the general population. Different strategies to improve glycemic control involve the prescription of blood glucose-lowering drugs and the modulation of physical activity and diet. Interestingly, lifestyle intervention may be more effective in lowering hyperglycemia than pharmaceutical intervention.

Ovarian cancer ascites induces skeletal muscle wasting in vitro and reflects sarcopenia in patients.

Background: Cachexia-associated skeletal muscle wasting or 'sarcopenia' is highly prevalent in ovarian cancer and contributes to poor outcome. Drivers of cachexia-associated sarcopenia in ovarian cancer remain elusive, underscoring the need for novel and better models to identify tumour factors inducing sarcopenia. We aimed to assess whether factors present in ascites of sarcopenic vs.

Hepatic Steatosis Contributes to the Development of Muscle Atrophy Inter-Organ Crosstalk.

Individuals with hepatic steatosis often display several metabolic abnormalities including insulin resistance and muscle atrophy. Previously, we found that hepatic steatosis results in an altered hepatokine secretion profile, thereby inducing skeletal muscle insulin resistance inter-organ crosstalk. In this study, we aimed to investigate whether the altered secretion profile in the state of hepatic steatosis also induces skeletal muscle atrophy effects on muscle protein turnover.

L-arabinose co-ingestion delays glucose absorption derived from sucrose in healthy men and women: a double-blind, randomised crossover trial.

Dietary interventions to delay carbohydrate digestion or absorption can effectively prevent hyperglycaemia in the early postprandial phase. L-arabinose can specifically inhibit sucrase. It remains to be assessed whether co-ingestion of L-arabinose with sucrose delays sucrose digestion, attenuates subsequent glucose absorption and impacts hepatic glucose output.

SMOC1 is a glucose-responsive hepatokine and therapeutic target for glycemic control.

Intertissue communication is a fundamental feature of metabolic regulation, and the liver is central to this process. We have identified sparc-related modular calcium-binding protein 1 (SMOC1) as a glucose-responsive hepatokine and regulator of glucose homeostasis. Acute intraperitoneal administration of SMOC1 improved glycemic control and insulin sensitivity in mice without changes in insulin secretion.

Mitochondrial Dysfunction is a Key Pathway that Links Saturated Fat Intake to the Development and Progression of NAFLD.

Non-Alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and is characterized by fat accumulation in the liver. Hypercaloric diets generally increase hepatic fat accumulation, whereas hypocaloric diets decrease liver fat content. In addition, there is evidence to suggest that moderate amounts of unsaturated fatty acids seems to be protective for the development of a fatty liver, while consumption of saturated fatty acids (SFA) appears to predispose toward hepatic steatosis.

Lipotoxicity plays a key role in the development of both insulin resistance and muscle atrophy in patients with type 2 diabetes.

Insulin resistance and muscle mass loss often coincide in individuals with type 2 diabetes. Most patients with type 2 diabetes are overweight, and it is well established that obesity and derangements in lipid metabolism play an important role in the development of insulin resistance in these individuals. Specifically, increased adipose tissue mass and dysfunctional adipose tissue lead to systemic lipid overflow and to low-grade inflammation via altered secretion of adipokines and cytokines.

An integrative systems genetic analysis of mammalian lipid metabolism.

Dysregulation of lipid homeostasis is a precipitating event in the pathogenesis and progression of hepatosteatosis and metabolic syndrome. These conditions are highly prevalent in developed societies and currently have limited options for diagnostic and therapeutic intervention. Here, using a proteomic and lipidomic-wide systems genetic approach, we interrogated lipid regulatory networks in 107 genetically distinct mouse strains to reveal key insights into the control and network structure of mammalian lipid metabolism.

Gut microbial metabolites in obesity, NAFLD and T2DM.

Evidence is accumulating that the gut microbiome is involved in the aetiology of obesity and obesity-related complications such as nonalcoholic fatty liver disease (NAFLD), insulin resistance and type 2 diabetes mellitus (T2DM). The gut microbiota is able to ferment indigestible carbohydrates (for example, dietary fibre), thereby yielding important metabolites such as short-chain fatty acids and succinate. Numerous animal studies and a handful of human studies suggest a beneficial role of these metabolites in the prevention and treatment of obesity and its comorbidities.

Perilipin 5 Deletion in Hepatocytes Remodels Lipid Metabolism and Causes Hepatic Insulin Resistance in Mice.

Defects in hepatic lipid metabolism cause nonalcoholic fatty liver disease and insulin resistance, and these pathologies are closely linked. Regulation of lipid droplet metabolism is central to the control of intracellular fatty acid fluxes, and perilipin 5 (PLIN5) is important in this process. We examined the role of PLIN5 on hepatic lipid metabolism and systemic glycemic control using liver-specific -deficient mice ( ).

Distinct lipid droplet characteristics and distribution unmask the apparent contradiction of the athlete's paradox.

Objective: Intramyocellular lipid (IMCL) storage negatively associates with insulin resistance, albeit not in endurance-trained athletes. We investigated the putative contribution of lipid droplet (LD) morphology and subcellular localization to the so-called athlete's paradox.

Methods: We performed quantitative immunofluorescent confocal imaging of muscle biopsy sections from endurance Trained, Lean sedentary, Obese, and Type 2 diabetes (T2DM) participants (n = 8/group).

Absence of renal hypoxia in the subacute phase of severe renal ischemia-reperfusion injury.

Tissue hypoxia has been proposed as an important event in renal ischemia-reperfusion injury (IRI), particularly during the period of ischemia and in the immediate hours following reperfusion. However, little is known about renal oxygenation during the subacute phase of IRI. We employed four different methods to assess the temporal and spatial changes in tissue oxygenation during the subacute phase (24 h and 5 days after reperfusion) of a severe form of renal IRI in rats.

Mitochondrial dysfunction-related lipid changes occur in nonalcoholic fatty liver disease progression.

Nonalcoholic fatty liver disease (NAFLD) comprises fat-accumulating conditions within hepatocytes that can cause severe liver damage and metabolic comorbidities. Studies suggest that mitochondrial dysfunction contributes to its development and progression and that the hepatic lipidome changes extensively in obesity and in NAFLD. To gain insight into the relationship between lipid metabolism and disease progression through different stages of NAFLD, we performed lipidomic analysis of plasma and liver biopsy samples from obese patients with nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH) and from those without NAFLD.

Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance.

Hepatic steatosis is an underlying feature of nonalcoholic fatty liver disease (NAFLD), which is the most common form of liver disease and is present in up to ∼70% of individuals who are overweight. NAFLD is also associated with hypertriglyceridaemia and low levels of HDL, glucose intolerance, insulin resistance and type 2 diabetes mellitus. Hepatic steatosis is a strong predictor of the development of insulin resistance and often precedes the onset of other known mediators of insulin resistance.

Impact of endurance exercise training on adipocyte microRNA expression in overweight men.

Adipocytes are major regulators of metabolism, and endurance exercise training improves adipocyte function; however, the molecular mechanisms that regulate chronic adaptive responses remain unresolved. microRNAs (miRNAs) influence adipocyte differentiation and metabolism. Accordingly, we aimed to determine whether adipocyte miRNA expression is responsive to exercise training and to identify exercise-responsive miRNAs that influence adipocyte metabolism.

Fetuin B Is a Secreted Hepatocyte Factor Linking Steatosis to Impaired Glucose Metabolism.

Liver steatosis is associated with the development of insulin resistance and the pathogenesis of type 2 diabetes. We tested the hypothesis that protein signals originating from steatotic hepatocytes communicate with other cells to modulate metabolic phenotypes. We show that the secreted factors from steatotic hepatocytes induce pro-inflammatory signaling and insulin resistance in cultured cells.

ATGL-mediated triglyceride turnover and the regulation of mitochondrial capacity in skeletal muscle.

Emerging evidence indicates that skeletal muscle lipid droplets are an important control point for intracellular lipid homeostasis and that regulating fatty acid fluxes from lipid droplets might influence mitochondrial capacity. We used pharmacological blockers of the major triglyceride lipases, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase, to show that a large proportion of the fatty acids that are transported into myotubes are trafficked through the intramyocellular triglyceride pool. We next tested whether increasing lipolysis from intramyocellular lipid droplets could activate transcriptional responses to enhance mitochondrial and fatty acid oxidative capacity.

Cellular localization and associations of the major lipolytic proteins in human skeletal muscle at rest and during exercise.

Lipolysis involves the sequential breakdown of fatty acids from triacylglycerol and is increased during energy stress such as exercise. Adipose triglyceride lipase (ATGL) is a key regulator of skeletal muscle lipolysis and perilipin (PLIN) 5 is postulated to be an important regulator of ATGL action of muscle lipolysis. Hence, we hypothesized that non-genomic regulation such as cellular localization and the interaction of these key proteins modulate muscle lipolysis during exercise.

Relationship of C5L2 receptor to skeletal muscle substrate utilization.

Objective: To investigate the role of Acylation Stimulating Protein (ASP) receptor C5L2 in skeletal muscle fatty acid accumulation and metabolism as well as insulin sensitivity in both mice and human models of diet-induced insulin resistance.

Design And Methods: Male wildtype (WT) and C5L2 knockout (KO) mice were fed a low (LFD) or a high (HFD) fat diet for 10 weeks. Intramyocellular lipid (IMCL) accumulation (by oil red O staining) and beta-oxidation HADH enzyme activity were determined in skeletal muscle.

Relationships between mitochondrial function and metabolic flexibility in type 2 diabetes mellitus.

Introduction: Mitochondrial dysfunction, lipid accumulation, insulin resistance and metabolic inflexibility have been implicated in the etiology of type 2 diabetes (T2D), yet their interrelationship remains speculative. We investigated these interrelationships in a group of T2D and obese normoglycemic control subjects.

Methods: 49 non-insulin dependent male T2D patients and 54 male control subjects were enrolled, and a hyperinsulinemic-euglycemic clamp and indirect calorimetry were performed.

PPARγ coactivator-1α contributes to exercise-induced regulation of intramuscular lipid droplet programming in mice and humans.

Intramuscular accumulation of triacylglycerol, in the form of lipid droplets (LD), has gained widespread attention as a hallmark of metabolic disease and insulin resistance. Paradoxically, LDs also amass in muscles of highly trained endurance athletes who are exquisitely insulin sensitive. Understanding the molecular mechanisms that mediate the expansion and appropriate metabolic control of LDs in the context of habitual physical activity could lead to new therapeutic opportunities.