Patrik Löfgren

Evidence for an important role of perilipin in the regulation of human adipocyte lipolysis.

Aims/hypothesisWe investigated the role of the adipocyte-specific protein perilipin for lipolysis in humans.MethodsPerilipin protein content and lipolysis rates were measured in human subcutaneous fat cells of non-obese (n=10) and obese (n=117) women. Single nucleotide polymorphisms in the perilipin gene were examined in obese subjects.ResultsBasal and noradrenaline-induced rates of lipolysis were two to fourfold increased (p<0.01) and perilipin protein content decreased 50% (p=0.005) in adipocytes of the obese women. In subjects matched for body mass index and fat-cell volume, a high rate of lipolysis was associated with a low adipocyte content of perilipin (p=0.01). Adipocyte content of perilipin was inversely correlated with the circulating concentrations of glycerol (r=0.62) and non-esterified fatty acids (n=0.49). A gene polymorphism (rs891460 A/G) in intron 6 was common. In AA subjects basal and noradrenaline induced lipolysis were 50 to 100% times more rapid (p≤0.01) and the adipocyte perilipin content was about 80% reduced (p=0.005) as compared to GG carriers. Intermediate values were found in AG carriers.Conclusions/interpretationPerilipin seems important for the regulation of lipolysis in human fat cells. Obesity and a polymorphism in the perilipin gene associate with decreased protein content of perilipin and increased basal (unstrained) and noradrenaline-induced lipolysis. Low perilipin content also associate with high in vivo lipolytic activity. Perilipin could be a factor behind impaired lipolysis in insulin-resistant conditions.

Regional impact of adipose tissue morphology on the metabolic profile in morbid obesity

Aims/hypothesisThe aim of this study was to determine whether the mean size of fat cells in either visceral or subcutaneous adipose tissue has an impact on the metabolic and inflammatory profiles in morbid obesity.MethodsIn 80 morbidly obese women, mean visceral (omental) and subcutaneous fat cell sizes were related to in vivo markers of inflammation, glucose metabolism and lipid metabolism.ResultsVisceral, but not subcutaneous, adipocyte size was significantly associated with plasma apolipoprotein B, total cholesterol, LDL-cholesterol and triacylglycerols (p ranging from 0.002 to 0.015, partial r ranging from 0.3 to 0.4). Subcutaneous, but not visceral, adipocyte size was significantly associated with plasma insulin and glucose, insulin-induced glucose disposal and insulin sensitivity (p ranging from 0.002 to 0.005, partial r ranging from −0.34 to 0.35). The associations were independent of age, BMI, body fat mass or body fat distribution. Adipose tissue hyperplasia (i.e. many small adipocytes) in both regions was significantly associated with better glucose, insulin and lipid profiles compared with adipose hypertrophy (i.e. few large adipocytes) in any or both regions (p ranging from <0.0001 to 0.04). Circulating inflammatory markers were not associated with fat cell size or corresponding gene expression in the fat cell regions examined.Conclusions/interpretationIn morbidly obese women region-specific variations in mean adipocyte size are associated with metabolic complications but not systemic or adipose inflammation. Large fat cells in the visceral region are linked to dyslipidaemia, whereas large subcutaneous adipocytes are important for glucose and insulin abnormalities. Hyperplasia (many small adipocytes) in both adipose regions may be protective against lipid as well as glucose/insulin abnormalities in obesity.

Prospective and controlled studies of the actions of insulin and catecholamine in fat cells of obese women following weight reduction

Aims/hypothesisEnlarged fat cells from obese subjects are characterised by insulin resistance and abnormal adrenergic regulation of lipolysis. The aim of the present study was to examine whether these aberrations return to normal following weight reduction.Materials and methodsObese women (n=25) were investigated before and 3±1 years (mean±SD) after steady-state weight reduction and compared with control women who were matched to the cases at re-examination in terms of age and BMI. Adipocyte volume, lipogenesis and lipolysis were determined in isolated subcutaneous fat cells following stimulation or inhibition at different steps of the lipolytic cascade.ResultsWeight reduction decreased fat cell volume and basal and adrenergic-regulated lipolysis rates to values that were 20–40% lower than those in control women (p=0.0002–0.03), despite the fact that percentage body fat was almost identical in the two groups of women. Fat cell volume was directly proportional to lipolysis in obese subjects, both before and after weight reduction, and in control subjects. Insulin-induced antilipolysis and lipogenesis were completely normalised after weight reduction.Conclusions/interpretationBody-weight-reduced obese women had low basal and catecholamine-stimulated adipocyte lipolysis, presumably due to adipose tissue hyperplasia. This could make an important contribution to body weight gain following weight loss. Adipocyte insulin resistance is secondary to obesity.

Changes in Subcutaneous Fat Cell Volume and Insulin Sensitivity After Weight Loss

OBJECTIVE Large subcutaneous fat cells associate with insulin resistance and high risk of developing type 2 diabetes. We investigated if changes in fat cell volume and fat mass correlate with improvements in the metabolic risk profile after bariatric surgery in obese patients. RESEARCH DESIGN AND METHODS Fat cell volume and number were measured in abdominal subcutaneous adipose tissue in 62 obese women before and 2 years after Roux-en-Y gastric bypass (RYGB). Regional body fat mass by dual-energy X-ray absorptiometry; insulin sensitivity by hyperinsulinemic-euglycemic clamp; and plasma glucose, insulin, and lipid profile were assessed. RESULTS RYGB decreased body weight by 33%, which was accompanied by decreased adipocyte volume but not number. Fat mass in the measured regions decreased and all metabolic parameters were improved after RYGB (P < 0.0001). Whereas reduced subcutaneous fat cell size correlated strongly with improved insulin sensitivity (P = 0.0057), regional changes in fat mass did not, except for a weak correlation between changes in visceral fat mass and insulin sensitivity and triglycerides. The curve-linear relationship between fat cell size and fat mass was altered after weight loss (P = 0.03). CONCLUSIONS After bariatric surgery in obese women, a reduction in subcutaneous fat cell volume associates more strongly with improvement of insulin sensitivity than fat mass reduction per se. An altered relationship between adipocyte size and fat mass may be important for improving insulin sensitivity after weight loss. Fat cell size reduction could constitute a target to improve insulin sensitivity.

Visceral Fat Cell Lipolysis and Cardiovascular Risk Factors in Obesity

Visceral fat accumulation relates to cardiovascular risk factors, but the underlying mechanisms are not well understood. We investigated the role of visceral adipocyte triglyceride breakdown (lipolysis) for several risk factors of cardiovascular disease. In 73 obese women, fat mass and distribution, blood pressure, blood samples for cardiometabolic risk factors, and whole-body insulin sensitivity were determined. A subcutaneous and a visceral fat biopsy were taken. Fat cell glycerol release after stimulation with a major lipolytic hormone, noradrenaline, was measured. In simple regression analysis, visceral fat cell lipolysis, but not subcutaneous adipocyte lipolysis was related to components of the metabolic syndrome. Moreover, subjects in the highest quartile of catecholamine-induced visceral lipolysis had higher levels of systolic blood pressure, estimated liver fat, plasma levels of glucose, insulin, cholesterol, LDL-cholesterol, triglycerides and apolipoprotein B and lower whole-body insulin sensitivity than those in the lowest quartile (p=0.0004-0.048). Among subjects with the metabolic syndrome, visceral fat cell lipolysis was 40% higher than in the remaining subjects (p=0.0052). Catecholamine-activated lipolysis in visceral but not subcutaneous fat cells is associated with cardiovascular risk factors in obesity.

Diabetes Mellitus Is Associated With Reduced High-Density Lipoprotein Sphingosine-1-Phosphate Content and Impaired High-Density Lipoprotein Cardiac Cell Protection

Objective—The dyslipidemia of type 2 diabetes mellitus has multiple etiologies and impairs lipoprotein functionality, thereby increasing risk for cardiovascular disease. High-density lipoproteins (HDLs) have several beneficial effects, notably protecting the heart from myocardial ischemia. We hypothesized that glycation of HDL could compromise this cardioprotective effect. Approach and Results—We used in vitro (cardiomyocytes) and ex vivo (whole heart) models subjected to oxidative stress together with HDL isolated from diabetic patients and nondiabetic HDL glycated in vitro (methylglyoxal). Diabetic and in vitro glycated HDL were less effective (P<0.05) than control HDL in protecting from oxidative stress. Protection was significantly, inversely correlated with the degree of in vitro glycation (P<0.001) and the levels of hemoglobin A1c in diabetic patients (P<0.007). The ability to activate protective, intracellular survival pathways involving Akt, Stat3, and Erk1/2 was significantly reduced (P<0.05) using glycated HDL. Glycation reduced the sphingosine-1-phosphate (S1P) content of HDL, whereas the S1P concentrations of diabetic HDL were inversely correlated with hemoglobin A1c (P<0.005). The S1P contents of in vitro glycated and diabetic HDL were significantly, positively correlated (both <0.01) with cardiomyocyte survival during oxidative stress. Adding S1P to diabetic HDL increased its S1P content and restored its cardioprotective function. Conclusions—Our data demonstrate that glycation can reduce the S1P content of HDL, leading to increased cardiomyocyte cell death because of less effective activation of intracellular survival pathways. It has important implications for the functionality of HDL in diabetes mellitus because HDL-S1P has several beneficial effects on the vasculature.

Increased visceral adipocyte lipolysis--a pathogenic role in nonalcoholic fatty liver disease?

CONTEXT Obesity is a major risk factor for nonalcoholic fatty liver disease, but the primary pathophysiological mechanisms remain unclear. OBJECTIVE The aim was to study the relative role of visceral and sc in vitro lipolysis for liver fat accumulation. PATIENTS Eighteen morbidly obese women participated in the study. DESIGN Hepatic triglyceride accumulation and abdominal visceral and sc fat area were assessed by computer tomography. Biopsies were taken from abdominal sc and visceral fat tissue. Basal and maximal lipolysis was measured using various lipolytic drugs acting at different steps in the lipolytic cascade. RESULTS No difference in total body, visceral, or sc fat mass was found between patients with high, intermediate, or low amounts of liver fat. In patients with high liver fat content, there was an approximately 2-fold increase in visceral adipocyte maximal glycerol release induced by the different lipolytic agents (P = 0.002 to 0.01). Noradrenaline-mediated free fatty acid release from visceral adipocytes was also about twice as high in patients with high liver fat (P = 0.004). In contrast, in sc adipocytes, no relationship between liver fat content and either glycerol or free fatty acid release was found. CONCLUSIONS We suggest a pathogenic role of visceral, but not sc, adipocyte lipolytic function in nonalcoholic fatty liver disease, independent of total body fat as well as abdominal fat distribution.

Lipolysis index: evaluation of a new tool for metabolic assessment in epidemiological studies on obesity.

Lipid mobilization through adipocyte lipolysis is central for energy metabolism and is decreased in obesity. However, the factors of importance for lipolytic activity in the general population are not known. To further examine this we performed a cross-sectional study on teenagers and adults. We constructed and evaluated a simple index of lipolytic activity (ratio of fasting p-glycerol and body fat %) in population based samples in 316 teenagers (BMI 16-51 kg/m (2)) and 3,039 adults (BMI 16-70 kg/m (2)). In the adults, multiple regression analysis showed that waist and BMI but not age, plasma insulin, plasma noradrenaline or waist-to-hip ratio contributed independently and inversely to lipolytic activity (partial r=-0.37 and -0.28, respectively, p<0.0001). Together waist and BMI explained about 45% of the variability of lipolysis. Waist was a stronger factor than BMI in stepwise regression. The same analysis in teenagers showed that only BMI contributed independently and inversely to lipolytic activity (partial r=-0.90, p<0.0001) and explained about 55% of lipolysis variation. BMI had the strongest effect on lipolysis in lean teenagers. The results were the same for men and women. At all levels of lipolytic activity plasma fatty acid levels were elevated in obese subjects (p<0.0001). We conclude that during adolescence BMI is the major factor negatively influencing lipolytic activity, in particular among lean young subjects. In adulthood central fat accumulation together with increasing BMI decreases lipolysis. In spite of low lipolytic activity circulating fatty acid levels are increased in obesity, probably due to an adipose mass effect.