Accumulation of lipid in skeletal muscle is thought to be related to the development of insulin resistance and type 2 diabetes. Initial work in this area focused on accumulation of intramuscular ...triglyceride; however, bioactive lipids such as diacylglycerols and sphingolipids are now thought to play an important role. Specific species of these lipids appear to be more negative toward insulin sensitivity than others. Adding another layer of complexity, localization of lipids within the cell appears to influence the relationship between these lipids and insulin sensitivity. This article summarizes how accumulation of total lipids, specific lipid species, and localization of lipids influence insulin sensitivity in humans. We then focus on how these aspects of muscle lipids are impacted by acute and chronic aerobic and resistance exercise training. By understanding how exercise alters specific species and localization of lipids, it may be possible to uncover specific lipids that most heavily impact insulin sensitivity.
People commonly increase sleep duration on the weekend to recover from sleep loss incurred during the workweek. Whether ad libitum weekend recovery sleep prevents metabolic dysregulation caused by ...recurrent insufficient sleep is unknown. Here, we assessed sleep, circadian timing, energy intake, weight gain, and insulin sensitivity during sustained insufficient sleep (9 nights) and during recurrent insufficient sleep following ad libitum weekend recovery sleep. Healthy, young adults were randomly assigned to one of three groups: (1) control (CON; 9-h sleep opportunities, n = 8), (2) sleep restriction without weekend recovery sleep (SR; 5-h sleep opportunities, n = 14), and (3) sleep restriction with weekend recovery sleep (WR; insufficient sleep for 5-day workweek, then 2 days of weekend recovery, then 2 nights of insufficient sleep, n = 14). For SR and WR groups, insufficient sleep increased after-dinner energy intake and body weight versus baseline. During ad libitum weekend recovery sleep, participants cumulatively slept ∼1.1 h more than baseline, and after-dinner energy intake decreased versus insufficient sleep. However, during recurrent insufficient sleep following the weekend, the circadian phase was delayed, and after-dinner energy intake and body weight increased versus baseline. In SR, whole-body insulin sensitivity decreased ∼13% during insufficient sleep versus baseline, and in WR, whole-body, hepatic, and muscle insulin sensitivity decreased ∼9%–27% during recurrent insufficient sleep versus baseline. Furthermore, during the weekend, total sleep duration was lower in women versus men, and energy intake decreased to baseline levels in women but not in men. Our findings suggest that weekend recovery sleep is not an effective strategy to prevent metabolic dysregulation associated with recurrent insufficient sleep.
•Sleep loss increased after-dinner energy intake and reduced insulin sensitivity•In total, participants slept an extra 1.1 h during weekend recovery versus baseline•After-dinner energy intake was reduced during weekend recovery sleep•Weekend recovery sleep did not prevent weight gain or reduced insulin sensitivity
Weekend recovery sleep is a common sleep-loss countermeasure. Depner et al. show that short sleep led to later timing of energy intake, weight gain, and reduced insulin sensitivity. Weekend recovery sleep failed to prevent later timing of energy intake, weight gain, or reduced insulin sensitivity during recurrent short sleep following the weekend.
Skeletal muscle fat infiltration (known as myosteatosis) is an ectopic fat depot that increases with aging and is recognized to negatively correlate with muscle mass, strength, and mobility and ...disrupt metabolism (insulin resistance, diabetes). An interdisciplinary workshop convened by the National Institute on Aging Division of Geriatrics and Clinical Gerontology on September 2018, discussed myosteatosis in the context of skeletal muscle function deficit (SMFD). Its purpose was to gain a better understanding of the roles of myosteatosis in aging muscles and metabolic disease, particularly its potential determinants and clinical consequences, and ways of properly assessing it. Special attention was given to functional status and standardization of measures of body composition (including the value of D
-creatine dilution method) and imaging approaches including ways to better use dual-energy X-ray absorptiometry (DXA) through the shape and appearance modeling to assess lean mass, sarcopenia, and myosteatosis. The workshop convened innovative new areas of scientific relevance to light such as the effect of circadian rhythms and clock disruption in skeletal muscle structure, function, metabolism, and potential contribution to increased myosteatosis. A muscle-bone interaction perspective compared mechanisms associated with myosteatosis and bone marrow adiposity. Potential preventive and therapeutic approaches highlighted ongoing work on physical activity, myostatin treatment, and calorie restriction. Myosteatosis' impact on cancer survivors raised new possibilities to identify its role and to engage in cross-disciplinary collaboration. A wide range of research opportunities and challenges in planning for the most appropriate study design, interpretation, and translation of findings into clinical practice were discussed and are presented here.
Alterations in adipose tissue composition and function are associated with obesity and contribute to the development of type 2 diabetes. While the significance of this relationship has been cemented, ...our understanding of the multifaceted role of adipose tissue in metabolic heath and disease continues to evolve and expand. Heterogenous populations of cells that make up adipose tissue throughout the body generate diverse secretomes containing a mosaic of bioactive compounds with vast structural and signaling capabilities. While there are many reports highlighting the important role of adipose tissue endocrine signaling in insulin resistance and type 2 diabetes, the direct, local, paracrine effect of adipose tissue has received less attention. Recent studies have begun to underscore the importance of considering anatomically discrete adipose depots for their specific impact on local microenvironments and metabolic function in neighboring tissues as well as regulation of whole-body physiology. This article highlights the important role of adipose tissue paracrine signaling on metabolic function and insulin sensitivity in nearby tissues and organs, specifically focusing on visceral, pancreatic, subcutaneous, intermuscular, and perivascular adipose tissue depots.
Highlights
Despite the common practice of switching patients from one medicine to another—to improve efficacy, safety, or tolerability—guidance on how to do so is uncommon. During this time of global ...shortage of glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA) ± glucose‐dependent insulinotropic polypeptide (GIP) RA therapies, this research letter offers a quick clinical reference of rough equivalency between GLP‐1 ± GIP RA for A1c and body weight reduction in people with type 2 diabetes.
Intermuscular adipose tissue (IMAT) is negatively related to insulin sensitivity, but a causal role of IMAT in the development of insulin resistance is unknown. IMAT was sampled in humans to test for ...the ability to induce insulin resistance in vitro and characterize gene expression to uncover how IMAT may promote skeletal muscle insulin resistance. Human primary muscle cells were incubated with conditioned media from IMAT, visceral (VAT), or subcutaneous adipose tissue (SAT) to evaluate changes in insulin sensitivity. RNAseq analysis was performed on IMAT with gene expression compared with skeletal muscle and SAT, and relationships to insulin sensitivity were determined in men and women spanning a wide range of insulin sensitivity measured by hyperinsulinemic-euglycemic clamp. Conditioned media from IMAT and VAT decreased insulin sensitivity similarly compared with SAT. Multidimensional scaling analysis revealed distinct gene expression patterns in IMAT compared with SAT and muscle. Pathway analysis revealed that IMAT expression of genes in insulin signaling, oxidative phosphorylation, and peroxisomal metabolism related positively to donor insulin sensitivity, whereas expression of macrophage markers, inflammatory cytokines, and secreted extracellular matrix proteins were negatively related to insulin sensitivity. Perilipin 5 gene expression suggested greater IMAT lipolysis in insulin-resistant individuals. Combined, these data show that factors secreted from IMAT modulate muscle insulin sensitivity, possibly via secretion of inflammatory cytokines and extracellular matrix proteins, and by increasing local FFA concentration in humans. These data suggest IMAT may be an important regulator of skeletal muscle insulin sensitivity and could be a novel therapeutic target for skeletal muscle insulin resistance.
Adipose tissues are not homogeneous and show site-specific properties. An elusive and understudied adipose tissue depot, most likely due to its limited accessibility, is the intermuscular adipose ...tissue (IMAT) depot. Adipose tissue is a pliable organ with the ability to adapt to its physiological context, yet whether that adaptation is harmful or beneficial in the IMAT depot remains to be explored in humans. Potential reasons for IMAT accumulation in humans being deleterious or beneficial include
) sex and related circulating hormone levels,
) race and ethnicity, and
) lifestyle factors (e.g., diet and physical activity level). IMAT quantity per se may not be the driving factor in the etiology of insulin resistance and type 2 diabetes, but rather the quality of the IMAT itself is the true puppeteer. Adipose tissue quality likely influences its secreted factors, which are also likely to influence metabolism of surrounding tissues. The advent of molecular assessments such as transcriptome sequencing (RNAseq), assay for transposase-accessible chromatin using sequencing (ATACseq), and DNA methylation at the single-cell and single-nucleus levels, as well as the potential for ultrasound-guided biopsies specifically for IMAT, will permit more sophisticated investigations of human IMAT and dramatically advance our understanding of this enigmatic adipose tissue.
Intermuscular adipose tissue (IMAT) is a distinct adipose depot described in early reports as a 'fatty replacement' or 'muscle fat infiltration' that was linked to ageing and neuromuscular disease. ...Later studies quantifying IMAT with modern in vivo imaging methods (computed tomography and magnetic resonance imaging) revealed that IMAT is proportionately higher in men and women with type 2 diabetes mellitus and the metabolic syndrome than in people without these conditions and is associated with insulin resistance and poor physical function with ageing. In parallel, agricultural research has provided extensive insight into the role of IMAT and other muscle lipids in muscle (that is, meat) quality. In addition, studies using rodent models have shown that IMAT is a bona fide white adipose tissue depot capable of robust triglyceride storage and turnover. Insight into the importance of IMAT in human biology has been limited by the dearth of studies on its biological properties, that is, the quality of IMAT. However, in the past few years, investigations have begun to determine that IMAT has molecular and metabolic features that distinguish it from other adipose tissue depots. These studies will be critical to further decipher the role of IMAT in health and disease and to better understand its potential as a therapeutic target.
Accumulation of muscle lipids promotes insulin resistance and type 2 diabetes (T2D). Ceramides are important muscle lipids that decrease insulin sensitivity and it was previously shown that ...accumulation of ceramides in the sarcolemma negatively impacts insulin sensitivity in humans. The mechanisms explaining accumulation of lipids in specific compartments in skeletal muscle are unknown, but one possibility is through circulating oxidized lipids. POVPC, a major circulating oxidized phospholipid, was exposed to rat myotubes (1-50 μM) for 4h and the total cellular ceramide levels in myotubes measured by LC-MS/MS. Total ceramide content increased dose dependently at POVPC doses in the physiological range (5 μM, p <0.05). To determine the mechanism of POVPC induced ceramide accumulation, ceramide was measured in myotubes after treatment with POVPC (25 μM) in the presence of inhibitors of neutral and acid sphingomyelinase (GW4869 and ARC39), ceramide synthase (fumonisin B1) and serine palmitoyltransferase (myriocin). The individually administered inhibitors in the presence of POVPC each showed a decrease (41-55%) in ceramide accumulation. When all of inhibitors were administered together along with POVPC, an almost complete inhibition of ceramide accumulation (95%) was observed indicating that the sphingomyelinase, de novo, and salvage pathways of ceramide synthesis are activated by POVPC. The role of oxidized lipids on insulin sensitivity was examined after treatment of rat myotubes with 1-25 μM POVPC. Increasing doses of POVPC at doses as low as 1 μM significantly decreased insulin sensitivity in vitro (p <0.05). These results reveal circulating oxidized lipids promote ceramide accumulation and insulin resistance in muscle cells and may help explain variability in total and localized muscle ceramide levels between individuals. These data also suggest that therapies designed to lower circulating oxidized lipids could be beneficial for the treatment and prevention of T2D.
Disclosure
K.Zemski berry: None. B.C.Bergman: Research Support; Eli Lilly and Company.
Funding
National Institutes of Health (P30DK048520); University of Colorado (25N0350)
The origins of nonalcoholic fatty liver disease (NAFLD) may lie in early intrauterine exposures. Here we examined the maternal response to chronic maternal high-fat (HF) diet and the impact of ...postweaning healthy diet on mechanisms for NAFLD development in juvenile nonhuman primate (NHP) offspring at 1 year of age. Pregnant females on HF diet were segregated as insulin resistant (IR; HF+IR) or insulin sensitive (IS; HF+IS) compared with control (CON)-fed mothers. HF+IR mothers have increased body mass, higher triglycerides, and increased placental cytokines. At weaning, offspring were placed on a CON or HF diet. Only offspring from HF+IR mothers had increased liver triglycerides and upregulated pathways for hepatic de novo lipid synthesis and inflammation that was irreversible upon switching to a healthy diet. These juvenile livers also showed a combination of classical and alternatively activated hepatic macrophages and natural killer T cells, in the absence of obesity or insulin resistance. Our findings suggest that maternal insulin resistance, including elevated triglycerides, insulin, and weight gain, initiates dysregulation of the juvenile hepatic immune system and development of de novo lipogenic pathways that persist in vitro and may be an irreversible "first hit" in the pathogenesis of NAFLD in NHP.
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