What have human experimental overfeeding studies taught us about adipose tissue expansion and susceptibility to obesity and metabolic complications?

Cuthbertson, Daniel J.; Steele, Tom; Wilding, John; Halford, Jason C.G.; Harrold, Jo; Hamer, Mark; Karpe, Fredrik

doi:10.1038/ijo.2017.4

Cited by 103 publications

(92 citation statements)

References 74 publications

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“…Body composition and metabolic cage studies Murine body composition was measured by 1 H magnetic resonance spectroscopy (Bruker, Billerica, MA, USA). Energy expenditure and caloric intake were measured in a Comprehensive Laboratory Animal Monitoring System (CLAMS; Columbus Instruments, Columbus, OH, USA).…”

Section: Mmttsmentioning

confidence: 99%

“…However, not all obese individuals are insulin resistant. This phenotypic heterogeneity may lie in differences in adipose biology [1]. Notably, some genes linked to forms of lipodystrophy are also dysregulated in individuals with more common forms of insulin resistance [2], lending genetic support for a key role for adipose dysfunction in individuals who develop insulin resistance [3].…”

Section: Introductionmentioning

confidence: 99%

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Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents

et al. 2018

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Aims/hypothesis Targeting regulators of adipose tissue lipoprotein lipase could enhance adipose lipid clearance, prevent ectopic lipid accumulation and consequently ameliorate insulin resistance and type 2 diabetes. Angiopoietin-like 8 (ANGPTL8) is an insulin-regulated lipoprotein lipase inhibitor strongly expressed in murine adipose tissue. However, Angptl8 knockout mice do not have improved insulin resistance. We hypothesised that pharmacological inhibition, using a second-generation antisense oligonucleotide (ASO) against Angptl8 in adult high-fat-fed rodents, would prevent ectopic lipid accumulation and insulin resistance by promoting adipose lipid uptake. Methods ANGPTL8 expression was assessed by quantitative PCR in omental adipose tissue of bariatric surgery patients. High-fatfed Sprague Dawley rats and C57BL/6 mice were treated with ASO against Angptl8 and insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamps in rats and glucose tolerance tests in mice. Factors mediating lipid-induced hepatic insulin resistance were assessed, including lipid content, protein kinase Cε (PKCε) activation and insulin-stimulated Akt phosphorylation. Rat adipose lipid uptake was assessed by mixed meal tolerance tests. Murine energy balance was assessed by indirect calorimetry. Results Omental fat ANGPTL8 mRNA expression is higher in obese individuals with fatty liver and insulin resistance compared with BMI-matched insulin-sensitive individuals. Angptl8 ASO prevented hepatic steatosis, PKCε activation and hepatic insulin resistance in high-fat-fed rats. Postprandial triacylglycerol uptake in white adipose tissue was increased in Angptl8 ASO-treated rats. Angptl8 ASO protected high-fat-fed mice from glucose intolerance. Although there was no change in net energy balance, Angptl8 ASO increased fat mass in high-fat-fed mice. Conclusions/interpretation Disinhibition of adipose tissue lipoprotein lipase is a novel therapeutic modality to enhance adipose lipid uptake and treat non-alcoholic fatty liver disease and insulin resistance. In line with this, adipose ANGPTL8 is a candidate therapeutic target for these conditions.

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Section: Mmttsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents

et al. 2018

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“…(2) Ectopic Muscle Fat Accumulation: Muscle lipid accumulation commonly occurs [30] as a result of insufficient adipose tissue expansion in the face of excess lipid availability [32]; convincing evidence has long demonstrated the close association of skeletal muscle lipid content with tissue and systemic insulin resistance [30,33]. Mechanisms mediating metabolic lipotoxicity are complex and appear to include direct pro-oxidative and inflammatory activities [28] as well as accumulation of metabolically toxic lipid moieties such as diacylglycerol and ceramides [34].…”

Section: Introduction: What We Knowmentioning

confidence: 99%

Sarcopenic Obesity: Time to Meet the Challenge

et al. 2018

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The prevalence of overweight and obesity has reached epidemic proportions worldwide due to increasingly pervasive obesogenic lifestyle changes. Obesity poses unprecedented individual, social, and multidisciplinary medical challenges by increasing the risk for metabolic diseases, chronic organ failures, and cancer as well as complication rates in the presence of acute disease conditions. Whereas reducing excess adiposity remains the fundamental pathogenic treatment for obese individuals, complex metabolic and lifestyle abnormalities as well as weight reduction therapies per se may also compromise the ability to preserve muscle function and mass, especially when chronic disease co-exists with obesity. Emerging evidence indicates that low muscle mass and quality have a strong negative prognostic impact in obese individuals and may lead to frailty, disability, and increased morbidity and mortality. Awareness of the importance of skeletal muscle maintenance in obesity is however low among clinicians and scientists. The term ‘sarcopenic obesity' has been proposed to identify obesity with low skeletal muscle function and mass, but its utilization is largely limited to the aging patient population, and consensus on its definition and diagnostic criteria remains insufficient. Knowledge on prevalence of sarcopenic obesity in various clinical conditions and patient subgroups, on its clinical impacts in patient risk stratification, and on effective prevention and treatment strategies remain therefore dramatically inadequate. In particular, optimal dietary options and medical nutritional support strategies to preserve muscle mass in obese individuals remain largely undefined. The European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) recognize and indicate obesity with altered body composition due to low skeletal muscle function and mass (sarcopenic obesity) as a scientific and clinical priority for researchers and clinicians. ESPEN and EASO therefore call for coordinated action aimed at reaching consensus on its definition, diagnostic criteria, and optimal treatment with particular regard to nutritional therapy. We are convinced that achievement of these goals has a strong potential to reduce the burden of morbidity and mortality in the rapidly increasing obese patient population.

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“…Genetics has been disappointing for clinical diabetes as it shifted from the early T2D candidate gene approach, which basically failed, to genome-wide association scanning and genomics, which showed that dozens of genes are involved in the predisposition to T2D (64)(65)(66). Furthermore, joint predisposition to T2D and comorbidities (principally, obesity [67], hypertension [68], and dyslipidemia [69]) has raised the task of identifying the genetic makeup of T2D to quasi-intractable levels of complexity. However, epigenetics and the "omics" (mainly metabolomics and proteomics) are providing increasingly more "physiological" profiles of diabetic subphenotypes by using integrated network methodology (70).…”

Section: What Does the Future Hold?mentioning

confidence: 99%

Diabetes Research and Care Through the Ages

et al. 2017

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As has been well established, the Diabetes Care journal’s most visible signature event is the Diabetes Care Symposium held each year during the American Diabetes Association’s Scientific Sessions. Held this past year on 10 June 2017 in San Diego, California, at the 77th Scientific Sessions, this event has become one of the most attended sessions during the Scientific Sessions. Each year, in order to continue to have the symposium generate interest, we revise the format and content of this event. For this past year, our 6th annual symposium, I felt it was time to provide a comprehensive overview of our efforts in diabetes care to determine, first and foremost, how we arrived at our current state of management. I also felt the narrative needed to include the current status of management, especially with a focus toward cardiovascular disease, and finally, we wanted to ask what the future holds. Toward this goal, I asked four of the most noted experts in the world to provide their opinion on this topic. The symposium started with a very thoughtful presentation by Dr. Jay Skyler entitled “A Look Back as to How We Got Here.” That was followed by two lectures on current concepts by Dr. Bernard Zinman entitled “Current Treatment Paradigms Today—How Well Are We Doing?” and by Dr. Matthew Riddle entitled “Evolving Concepts and Future Directions for Cardiovascular Outcomes Trials.” The final lecture for the symposium was delivered by Dr. Ele Ferrannini and was entitled “What Does the Future Hold?” As always, a well-attended and well-received symposium is now the norm for our signature event and our efforts were rewarded by the enthusiasm of the attendees. This narrative summarizes the lectures held at the symposium. —William T. Cefalu Chief Scientific, Medical & Mission Officer, American Diabetes Association

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What have human experimental overfeeding studies taught us about adipose tissue expansion and susceptibility to obesity and metabolic complications?

Cited by 103 publications

References 74 publications

Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents

Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents

Sarcopenic Obesity: Time to Meet the Challenge

Diabetes Research and Care Through the Ages

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