Context: An upper body/visceral fat distribution in obesity is closely linked with metabolic complications, whereas increased lower body fat is independently predictive of reduced cardiovascular ...risk.
Evidence Acquisition: The measured functions of different fat depots with regards to fatty acid storage and release in health and obesity were reviewed. The adverse effects of experimentally increasing free fatty acid (FFA) concentrations on liver, muscle, pancreatic β-cell, and endothelial function were noted.
Evidence Synthesis: The most dramatic abnormality in FFA metabolism is failure to suppress FFA concentrations/adipose tissue lipolysis normally in response to postprandial hyperinsulinemia. Upper body sc fat delivers the majority of FFA to the systemic circulation under postabsorptive and postprandial conditions. In upper body obesity, portal FFA concentrations resulting from both systemic and visceral adipose tissue lipolysis may be significantly greater than arterial FFA concentrations, exposing the liver to even greater amounts of FFA. Visceral fat also releases sufficient IL-6 to increase portal vein IL-6 concentrations, which can affect hepatic metabolism as well.
Conclusions: Lower body, upper body sc, and visceral fat depots have unique characteristics with regards to fatty acid metabolism. Selective dysregulation of these depots probably plays an important role with the metabolic complications of obesity.
Aging and metabolism are inextricably linked, and many age-related changes in body composition, including increased central adiposity and sarcopenia, have underpinnings in fundamental aging ...processes. These age-related changes are further exacerbated by a sedentary lifestyle and can be in part prevented by maintenance of activity with aging. Here we explore the age-related changes seen in individual metabolic tissues - adipose, muscle, and liver - as well as globally in older adults. We also discuss the available evidence for therapeutic interventions such as caloric restriction, resistance training, and senolytic and senomorphic drugs to maintain healthy metabolism with aging, focusing on data from human studies.
Fat distribution is closely linked to metabolic disease risk. Distribution varies with sex, genetic background, disease state, certain drugs and hormones, development, and aging. Preadipocyte ...replication and differentiation, developmental gene expression, susceptibility to apoptosis and cellular senescence, vascularity, inflammatory cell infiltration, and adipokine secretion vary among depots, as do fatty-acid handling and mechanisms of enlargement with positive-energy and loss with negative-energy balance. How interdepot differences in these molecular, cellular, and pathophysiological properties are related is incompletely understood. Whether fat redistribution causes metabolic disease or whether it is a marker of underlying processes that are primarily responsible is an open question.
Abstract
The prevalence of obesity, measured by body mass index, has risen to unacceptable levels in both men and women in the United States and worldwide with resultant hazardous health ...implications. Genetic, environmental, and behavioral factors influence the development of obesity, and both the general public and health professionals stigmatize those who suffer from the disease. Obesity is associated with and contributes to a shortened life span, type 2 diabetes mellitus, cardiovascular disease, some cancers, kidney disease, obstructive sleep apnea, gout, osteoarthritis, and hepatobiliary disease, among others. Weight loss reduces all of these diseases in a dose-related manner-the more weight lost, the better the outcome. The phenotype of "medically healthy obesity" appears to be a transient state that progresses over time to an unhealthy phenotype, especially in children and adolescents. Weight loss is best achieved by reducing energy intake and increasing energy expenditure. Programs that are effective for weight loss include peer-reviewed and approved lifestyle modification programs, diets, commercial weight-loss programs, exercise programs, medications, and surgery. Over-the-counter herbal preparations that some patients use to treat obesity have limited, if any, data documenting their efficacy or safety, and there are few regulatory requirements. Weight regain is expected in all patients, especially when treatment is discontinued. When making treatment decisions, clinicians should consider body fat distribution and individual health risks in addition to body mass index.
This Scientific Statement critically reviews the definition of obesity, providing a list of assessment methods, obesity-related diseases, and prevention measures.
Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and ...extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction.
Adipose tissue inflammation and dysfunction are associated with obesity‐related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells ...accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug‐inducible “suicide” genes driven by the p16Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra‐abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity‐related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity‐related metabolic dysfunction and its complications.
Obesity induces the formation of senescent cells, which contribute to inflammation, insulin resistance, and organ dysfunction. Senescent cell clearance may be an effective strategy for alleviating important elements of obesity‐related metabolic dysfunction.
How to Measure Adipose Tissue Insulin Sensitivity Søndergaard, Esben; Espinosa De Ycaza, Ana Elena; Morgan-Bathke, Maria ...
The journal of clinical endocrinology and metabolism,
2017-April-01, Letnik:
102, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Abstract
Context and Objective:
Adipose tissue insulin resistance may cause hepatic and skeletal muscle insulin resistance by releasing excess free fatty acids (FFAs). Because no consensus exists on ...how to quantify adipose tissue insulin sensitivity we compared three methods for measuring adipose tissue insulin sensitivity: the single step insulin clamp, the multistep pancreatic clamp, and the adipose tissue insulin resistance index (Adipo-IR).
Design and Participants:
We studied insulin sensitivity in 25 adults by measuring the insulin concentration resulting in 50% suppression of palmitate flux (IC50) using both a multistep pancreatic clamp and a one-step hyperinsulinemic-euglycemic clamp. Palmitate kinetics were measured using a continuous infusion of U-13Cpalmitate. Adipo-IR was calculated from fasting insulin and fasting FFA concentrations.
Results:
Adipo-IR was reproducible (sample coefficient of variability, 10.0%) and correlated with the IC50 measured by the multistep pancreatic clamp technique (r, 0.86; P < 0.001). Age and physical fitness were significant predictors of the residual variation between Adipo-IR and IC50, with a positive relationship with age (r, 0.47; P = 0.02) and a negative association with VO2 peak (r, −0.46; P = 0.02). Likewise, IC50 measured by the multistep pancreatic clamp technique correlated with IC50 measured using the one-step hyperinsulinemic-euglycemic clamp technique (r, 0.73; P < 0.001).
Conclusion:
Adipo-IR and the one-step hyperinsulinemic-euglycemic clamp technique using a palmitate tracer are good predictors of a gold standard measure of adipose tissue insulin sensitivity. However, age and physical fitness systematically affect the predictive values. Although Adipo-IR is suitable for larger population studies, the multistep pancreatic clamp technique is probably needed for mechanistic studies of adipose tissue insulin action.
A one-step hyperinsulinemic-euglycemic clamp with FFA tracers and Adipo-IR correlate with a gold standard measure of adipose insulin sensitivity, but age and physical fitness affect the relationships.
Body fat deposition and excess free fatty acid (FFA) metabolism contribute to dyslipidemia and the adverse health consequences of obesity. Individuals with upper body obesity have impaired ...functioning of adipocytes, the primary fatty acid storage site. Excess visceral fat is strongly associated with impaired suppression of FFA release in response to insulin, as well as with hypertriglyceridemia and low concentrations of high density lipoprotein (HDL) cholesterol. High FFA concentrations can induce insulin resistance in muscle and liver. Furthermore, failure of hyperinsulinemia to normally suppress FFA is associated with impaired carbohydrate oxidation and muscle glucose storage, reduced hepatic insulin clearance and elevated triglycerides. Understanding the impact of body fat distribution on FFA metabolism and dyslipidemia is critical for determining the link between overweight and obesity and cardiovascular disease risk. In the current review, we will explore the relationship between adipose tissue, body fat depots, and FFA metabolism.
Considerable evidence implicates cellular senescence in the biology of aging and chronic disease. Diet and exercise are determinants of healthy aging; however, the extent to which they affect the ...behavior and accretion of senescent cells within distinct tissues is not clear. Here we tested the hypothesis that exercise prevents premature senescent cell accumulation and systemic metabolic dysfunction induced by a fast-food diet (FFD). Using transgenic mice that express EGFP in response to activation of the senescence-associated p16(INK4a) promoter, we demonstrate that FFD consumption causes deleterious changes in body weight and composition as well as in measures of physical, cardiac, and metabolic health. The harmful effects of the FFD were associated with dramatic increases in several markers of senescence, including p16, EGFP, senescence-associated β-galactosidase, and the senescence-associated secretory phenotype (SASP) specifically in visceral adipose tissue. We show that exercise prevents the accumulation of senescent cells and the expression of the SASP while nullifying the damaging effects of the FFD on parameters of health. We also demonstrate that exercise initiated after long-term FFD feeding reduces senescent phenotype markers in visceral adipose tissue while attenuating physical impairments, suggesting that exercise may provide restorative benefit by mitigating accrued senescent burden. These findings highlight a novel mechanism by which exercise mediates its beneficial effects and reinforces the effect of modifiable lifestyle choices on health span.
Dysregulation of adipose tissue (AT) lipolysis, a hallmark of obesity and type 2 diabetes, results in elevated postabsorptive and postprandial plasma free fatty acid (FFA) concentrations. This is ...thought to be due to adipose insulin resistance with regards to anti-lipolysis effects. Alterations in intracellular adipocyte pathways and/or proteins that mediate this phenomenon in humans are poorly understood. To test the hypothesis that impaired insulin signaling is associated with adipose insulin resistance measured whole body insulin sensitivity (the insulin concentration that suppresses palmitate flux by 50% (IC50 FFA)) in 12 lean, 7 lower body obese and 15 upper body obese (n=15) volunteers using a single step hyperinsulinemic-euglycemic clamp. We also measured adipose pAkt/Akt (a measure of insulin signaling) and hormone sensitive lipase (pHSL/HSL) (a measure of lipolysis protein regulation) in biopsies of abdominal and thigh adipose obtained before and during the insulin clamp were measured. Contrary to our hypothesis, there was a positive relationship between IC50 FFA and insulin clamp fold change of pAkt/Akt in thigh samples (ρ = 0.38, p <0.05) and no relationship for abdominal adipose samples. There was good correlation between abdominal and thigh adipose samples in the fractional change in pAkt/Akt in response to insulin clamp (ρ= 0.49, p < 0.01). IC50 FFA was correlated to fractional decrease in HSL phosphorylation in both abdominal (r = 0.36, p< 0.05) and thigh (r = 0.41, p <0.05) Surprisingly, fold changes of pAKT/AKT in response to insulin clamp were positively correlated to fold change of pHSL/HSL in abdominal adipose tissue (ρ= 0.41, p < 0.05) but not thigh samples. In conclusion we found that insulin resistance in adipose is not related to canonical insulin signaling responses but is related to lipase responses.
Disclosure
K.Lytle: None. M.D.Jensen: Other Relationship; Novo Nordisk, Elsevier.
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DK40484)
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