Obesity: Lönnroth P

Dodt C, Lönnroth P, Wellhöner JP, Fehm HL, Elam M. · Department of Internal Medicine I, University of Lübeck, Germany. · Acta Physiol Scand. · Pubmed #12609006 No free full text.

Abstract: AIM: To induce lipolysis, catecholamines could reach the adipocyte via the blood stream after being released from the adrenal medulla or, alternatively, via neuronal release in the vicinity of the fat cell. Sympatho-neuronal effects on fat tissue lipolysis have been demonstrated in experimental animal models. However, the role of sympathetic nerves in the control of lipolysis in human white adipose tissue, which is sparsely innervated, has not been clarified. CONCLUSION: The present review summarizes evidence for a direct neuronal influence on lipolysis in humans.

Virtanen KA, Lönnroth P, Parkkola R, Peltoniemi P, Asola M, Viljanen T, Tolvanen T, Knuuti J, Rönnemaa T, Huupponen R, Nuutila P. · Turku PET Centre, University of Turku, Turku University Central Hospital, Turku 20521, Finland. · J Clin Endocrinol Metab. · Pubmed #12161530 links to  free full text

Abstract: To elucidate the role of adipose tissue glucose uptake in whole-body metabolism, sc and visceral adipose tissue glucose uptake and perfusion were measured in 10 nonobese and 10 age-matched obese men with positron emission tomography using [(18)F]-2-fluoro-2-deoxy-D-glucose, and [(15)O]-labeled water during normoglycemic hyperinsulinemia. Whole-body and skeletal muscle glucose uptake rates per kilogram were lower in obese than in nonobese subjects (P < 0.01). Compared with nonobese, the obese subjects had 67% lower abdominal sc and 58% lower visceral adipose tissue glucose uptake per kilogram of fat. In both groups, insulin stimulated glucose uptake per kilogram fat was significantly higher in visceral fat depots than in sc regions (P < 0.01). Both sc and visceral adipose tissue blood flow expressed per kilogram and minute was impaired in the obese subjects, compared with the nonobese (P < 0.05). Fat masses measured with magnetic resonance images were higher in obese than in nonobese individuals. If regional glucose uptake rates were expressed as per total fat mass, total glucose uptake rates per depot were similar in obese and nonobese subjects and represented 4.1% of whole-body glucose uptake in obese and 2.6% in nonobese subjects (P < 0.02 between the groups). In conclusion, insulin-stimulated glucose uptake per kilogram fat is higher in visceral than in sc adipose tissue. Glucose uptake and blood flow in adipose tissue exhibit insulin resistance in obesity, but because of the larger fat mass, adipose tissue does not seem to contribute substantially to the reduced insulin stimulated whole-body glucose uptake in obesity.

Murdolo G, Sjöstrand M, Strindberg L, Gudbjörnsdóttir S, Lind L, Lönnroth P, Jansson PA. · Department of Internal Medicine, Section of Internal Medicine, Endocrine and Metabolic Sciences, Perugia University, Via Enrico Dal Pozzo I, Perugia, Italy. · J Clin Endocrinol Metab. · Pubmed #18460559 links to  free full text

Abstract: CONTEXT: Impairment of insulin-mediated capillary recruitment in skeletal muscle contributes to a hampered glucose uptake in obesity. OBJECTIVE: The objective of this study was to evaluate whether metacholine (MCh), a nitric oxide vasodilator, potentiates muscle capillary recruitment and forearm glucose uptake (FGU) during physiological hyperinsulinemia. DESIGN: The double-forearm technique [i.e. infused vs. control (Ctrl) forearm] was combined with im microdialysis during an oral glucose tolerance test in 15 nondiabetic, obese subjects divided into a group of insulin-resistant (IR) (n = 7) and insulin-sensitive (n = 8) individuals. RESULTS: After the oral glucose tolerance test, forearm blood flow in the Ctrl forearm was unchanged, whereas it increased about 3-fold (P < 0.0001 vs. baseline) in response to MCh. Capillary permeability surface area product for glucose (PS(glu)) (capillary recruitment), FGU, and interstitial insulin concentrations increased significantly over time (P < 0.001) in both forearms. Compared with insulin-sensitive, the IR subjects exhibited lower PS(glu) (P < 0.001) and FGU (P < 0.01) in the Ctrl arm, whereas this difference was insignificant in the MCh arm despite the blunted forearm blood flow increase. Moreover, in IR individuals MCh significantly (P < 0.05) ameliorated the delayed onset of insulin action, i.e. the FGU response to hyperinsulinemia. Finally, we found PS(glu) to be a strong and independent predictor of FGU response (adjusted R(2) 0.72; P < 0.0001). CONCLUSIONS: MCh-induced vasodilation may improve the microvascular and metabolic responses to physiological hyperinsulinemia in obese, IR individuals. Further studies are required to unravel whether stimulation of nitric oxide production in skeletal muscle may represent an attractive therapeutic approach to bypassing cellular resistance to glucose disposal.

Wellhöner P, Rolle D, Lönnroth P, Strindberg L, Elam M, Dodt C. · Department of Internal Medicine, University of Schleswig Holstein, Luebeck, Germany. · Am J Physiol Endocrinol Metab. · Pubmed #16787964 links to  free full text

Abstract: The present study aimed to evaluate adipose tissue blood flow (ATBF) by means of laser-Doppler flowmetry (LDF) in humans. Lower body negative pressure (LBNP) and straining known to affect epidermal blood flow through the autonomic nervous system were performed in 11 lean and 11 obese female volunteers. ATBF changes were compared between both groups and also discriminated from skin blood flow (SBF) responses of the immediate vicinity. Additionally, LDF measurements were compared with flow measurements using (133)xenon washout in 10 lean subjects during whole body cooling. LDF estimations of SBF and ATBF showed a positive correlation to (133)Xe during cooling. SBF and ATBF were reduced to the same extent in both lean and obese subjects during LBNP. Straining induced divergent changes in SBF and ATBF: initially SBF decreased while ATBF increased, but toward the end of straining SBF increased above baseline and ATBF returned down to baseline level. Those changes were similar in both weight groups. Interestingly, only in obese subjects, both LBNP and straining were followed by ATBF augmentation, while SBF levels remained stable. In conclusion, LDF compares with (133)Xe washout in monitoring ATBF during tonic perfusion changes. Its strength, however, lies in the detection of rapid flow alterations within the subcutaneous tissue, allowing the evaluation of reflex responses of the subcutaneous microcirculation. Interestingly, those rapid changes in SBF and ATBF can be both concordant and discordant. With regard to ATBF, vasoconstrictor components of the reflex responses were similar in lean and obese subjects, whereas vasodilatory responses were more pronounced in obese volunteers.

Virtanen KA, Iozzo P, Hällsten K, Huupponen R, Parkkola R, Janatuinen T, Lönnqvist F, Viljanen T, Rönnemaa T, Lönnroth P, Knuuti J, Ferrannini E, Nuutila P. · Turku PET Centre, University of Turku, P.O. Box 52 20521, Turku, Finland. · Diabetes. · Pubmed #16123362 links to  free full text

Abstract: To evaluate the relative impact of abdominal obesity and newly diagnosed type 2 diabetes on insulin action in skeletal muscle and fat tissue, we studied 61 men with (n = 31) or without (n = 30) diabetes, subgrouped into abdominally obese or nonobese according to the waist circumference. Adipose tissue depots were quantified by magnetic resonance imaging, and regional glucose uptake was measured using 2-[(18)F]fluoro-2-deoxyglucose/positron emission tomography during euglycemic hyperinsulinemia. Across groups, glucose uptake per unit tissue weight was higher in visceral (20.5 +/- 1.4 micromol . min(-1) . kg(-1)) than in abdominal (9.8 +/- 0.9 micromol min(-1) . kg(-1), P < 0.001) or femoral (12.3 +/- 0.6 micromol . min(-1) . kg(-1), P < 0.001) subcutaneous tissue and approximately 40% lower than in skeletal muscle (33.1 +/- 2.5 micromol . min(-1) . kg(-1), P < 0.0001). Abdominal obesity was associated with a marked reduction in glucose uptake per unit tissue weight in all fat depots and in skeletal muscle (P < 0.001 for all regions). Recent type 2 diabetes per se had little additional effect. In both intra-abdominal adipose (r = -0.73, P < 0.0001) and skeletal muscle (r = -0.53, P < 0.0001) tissue, glucose uptake was reciprocally related to intra-abdominal fat mass in a curvilinear fashion. When regional glucose uptake was multiplied by tissue mass, total glucose uptake per fat depot was similar irrespective of abdominal obesity or type 2 diabetes, and its contribution to whole-body glucose uptake increased by approximately 40% in obese nondiabetic and nonobese diabetic men and was doubled in obese diabetic subjects. We conclude that 1) in abdominal obesity, insulin-stimulated glucose uptake rate is markedly reduced in skeletal muscle and in all fat depots; 2) in target tissues, this reduction is reciprocally (and nonlinearly) related to the amount of intra-abdominal fat; 3) mild, recent diabetes adds little insulin resistance to that caused by abdominal obesity; and 4) despite fat insulin resistance, an expanded fat mass (especially subcutaneous) provides a sink for glucose, resulting in a compensatory attenuation of insulin resistance at the whole-body level in men.

Sjöstrand M, Gudbjörnsdottir S, Holmäng A, Lönn L, Strindberg L, Lönnroth P. · Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital, Göteborg, Sweden. · Diabetes. · Pubmed #12196467 links to  free full text

Abstract: Insulin-resistant subjects have a slow onset of insulin action, and the underlying mechanism has not been determined. To evaluate whether a delayed transcapillary transport is part of the peripheral insulin resistance, we followed the kinetics of infused insulin and inulin in plasma and muscle interstitial fluid in obese insulin-resistant patients and control subjects. A total of 10 lean and 10 obese men (BMI 24 +/- 0.8 vs. 32 +/- 0.8 kg/m(2), P < 0.001) was evaluated during a hyperinsulinemic-euglycemic clamp (insulin infusion rate 120 mU. m(-2). min(-1)) combined with an inulin infusion. Measurements of insulin and inulin in plasma were taken by means of arterial-venous catheterization of the forearm and microdialysis in brachioradialis muscle combined with forearm blood flow measurements with vein occlusion pletysmography. The obese subjects had a significantly lower steady-state glucose infusion rate and, moreover, demonstrated a delayed appearance of insulin (time to achieve half-maximal concentration [T(1/2)] 72 +/- 6 vs. 46 +/- 6 min in control subjects, P < 0.05) as well as inulin (T(1/2) 83 +/- 3 vs. 53 +/- 7 min, P < 0.01) in the interstitial fluid. Also, the obese subjects had a delayed onset of insulin action (T(1/2) 70 +/- 9 vs. 45 +/- 5 min in control subjects, P < 0.05), and their forearm blood flow rate was significantly lower. These results demonstrate a delayed transcapillary transport of insulin and inulin from plasma to the muscle interstitial fluid and a delayed onset of insulin action in insulin-resistant obese subjects.

Sjöstrand M, Gudbjörnsdottir S, Holmäng A, Strindberg L, Ekberg K, Lönnroth P. · Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital, Göteborg S-413 45, Sweden. · J Clin Endocrinol Metab. · Pubmed #11994365 links to  free full text

Abstract: The aim of this project was to study the regulation of interstitial glycerol levels in muscle in normal subjects, and to estimate interstitial muscle glycerol in obese subjects and patients with type 2 diabetes. In healthy lean subjects, microdialysis of forearm sc and muscle tissue were combined with arterial and deep venous catheterization, as well as blood flow registrations during oral glucose ingestion. In two other separate studies, obese (n = 9) vs. lean (n = 10) subjects and type 2 diabetes patients (n = 8) vs. weight-matched control subjects (n = 8) were investigated by means of muscle microdialysis during a euglycemic hyperinsulinemic clamp. Oral glucose ingestion suppressed the interstitial sc glycerol concentration by approximately 40% (P < 0.05), whereas no significant reduction of muscle interstitial glycerol was found. In contrast to the significant muscle interstitial-arterial (I-A) glycerol difference, the venous-arterial difference was small and varying throughout the oral glucose tolerance test. At steady-state hyperinsulinemia, obese subjects' interstitial muscle glycerol and I-A glycerol difference were both significantly higher than lean controls, whereas type 2 diabetes patient had interstitial muscle glycerol concentrations and I-A glycerol differences similar to those found in weight-matched controls. A significant and marked I-A glycerol difference exists in the absence of a significant venous-arterial difference, indicating that muscle glycerol cannot be taken as a marker of intramyocellular lipolysis because local turnover of muscle glycerol might be significant. The present data also suggest that, in contrast to sc tissue, muscle tissue lacks a clear antilipolytic effect of insulin. Moreover, the muscle interstitial glycerol concentration is elevated in obese patients but does not precipitate insulin resistance and type 2 diabetes.

Dodt C, Lönnroth P, Fehm HL, Elam M. · Department of Internal Medicine I, Medical University of Lübeck, Germany. · Diabetes. · Pubmed #11078454 links to  free full text

Abstract: Disturbed fat tissue metabolism with a reduction of the lipolytic rate could be an important pathogenetic factor in obesity. Lipolysis of the subcutaneous tissue of the thigh is partly under neural control and can be increased by intraneural stimulation of the lateral cutaneous femoral nerve in lean women. In the present study, we tested whether the lipolytic response to intraneural stimulation is altered in vivo in obese subjects. Seven obese women were examined and the results were compared with those of seven age-matched lean women. After an overnight fast, the lateral cutaneous femoral nerve was intraneurally stimulated for 10 min, and the local subcutaneous lipolytic response to this procedure was evaluated with microdialytic measurements of interstitial glycerol concentrations in the receptive field of the stimulated nerve fascicle. To exclude unspecific effects of stimulation, lipolysis was also controlled in a corresponding area of the contralateral leg. Intraneural stimulation produced no significant change in subcutaneous lipolysis in obese women (25.7 +/- 9.7%, NS). This finding is in sharp contrast with the marked regional lipolytic response in lean women in which the same stimulation procedure enhanced the regional interstitial glycerol levels by 72 +/- 17% (P < 0.05) compared with the unstimulated corresponding area of the contralateral leg. These in vivo results suggest that human obesity is characterized by a profound unresponsiveness of the subcutaneous adipose tissue to neurally stimulated lipolysis. This could be an important factor in the development and treatment of obesity.

Peltoniemi P, Lönnroth P, Laine H, Oikonen V, Tolvanen T, Grönroos T, Strindberg L, Knuuti J, Nuutila P. · Turku Positron Emission Tomography Center, Department of Internal Medicine, University of Gothenburg, 41345 Gothenburg, Sweden. · Am J Physiol Endocrinol Metab. · Pubmed #11052968 links to  free full text

Abstract: Quantitative 2-[(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG) positron emission tomography (PET) has been widely used to calculate glucose utilization in skeletal muscle. FDG-PET results depend partly on the lumped constant (LC), which accounts for the differences in the transport and phosphorylation between [(18)F]FDG and glucose. In this study, we estimated the LC for [(18)F]FDG directly in normal and in insulin-resistant obese subjects by combining FDG PET with the microdialysis technique. Eight obese [age 29.4 +/- 1.0 yr, body mass index (BMI) 33.6 +/- 1.0 kg/m(2)] and eight nonobese (age 25.0 +/- 1.0 yr, BMI 23.1 +/- 1.0 kg/m(2)) males were studied during euglycemic hyperinsulinemia (1 mU. kg(-1).min(-1) for 150 min). Muscle blood flow was measured using (15)O-labeled water and PET. Muscle [(18)F]FDG uptake (rGU(FDG)) was calculated with Patlak graphic analysis. Interstitial glucose concentration of the quadriceps femoris muscle was measured simultaneously with [(18)F]FDG scanning using microdialysis. Muscle glucose uptake (by microdialysis, rGU(MD)) was calculated by multiplying glucose extraction by regional muscle blood flow. A significant correlation was found between rGU(MD) and rGU(FDG) (r = 0.78, P < 0.01). The LC was determined as the ratio of the rGU(FDG) to the rGU(MD). The LC averaged 1.16 +/- 0.16 and was similar in the obese and nonobese subjects (1.15 +/- 0.11 vs. 1.16 +/- 0.07, respectively, not significant). In conclusion, the microdialysis technique can be reliably combined with FDG PET to measure glucose uptake in skeletal muscle. Direct measurements with these two independent techniques suggest an LC value of 1.2 for [(18)F]FDG in human skeletal muscle during insulin stimulation, and the LC appears not to be sensitive to insulin resistance.

Børsheim E, Lönnroth P, Knardahl S, Jansson PA. · Norwegian University of Sport and Physical Education, Oslo, Norway. · Metabolism. · Pubmed #10831166 No free full text.

Abstract: This study was undertaken to determine the effect of previous exercise on adipose tissue responsiveness to beta-adrenoceptor stimulation and on adipose tissue blood flow (ATBF). Eight lean and 8 obese men (body mass index [BMI], 23.6 +/- 2.1 [SD] v 29.0 +/- 1.9 kg x m(-2)) were investigated with abdominal subcutaneous microdialysis and 133Xe clearance. A stepwise isoprenaline infusion (10(-8), 10(-7), and 10(-6) mol x L(-1)) was administered in situ in the microdialysis catheter before and 2 hours after a submaximal exercise bout (90 minutes of cycling at 55% of maximal O2 uptake). No differences in the response (increase in interstitial glycerol v preinfusion level) to isoprenaline infusions were found between the 2 groups. In both groups, there was no difference in the response to postexercise versus preexercise infusion. When the vasodilating agent hydralazine (0.125 g x L(-1)) was infused into the microdialysis catheter to control for the vascular effects of isoprenaline, an interaction effect between exercise and isoprenaline dose was found. Analyses showed an attenuated response to the high isoprenaline dose after exercise (lean, 251 +/- 42 [SE] micromol x L(-1); obese, 288 +/- 77 micromol x L(-1)) versus before exercise (lean, 352 +/- 62 micromol x L(-1), P = .045 v after; obese, 380 +/- 94 micromol x L(-1), P = .021 v after), indicating a desensitization of lipolysis to beta-adrenoceptor stimulation. ATBF and arterial plasma glycerol increased after exercise in both groups, but the increase was delayed in obese subjects. Arterial plasma insulin was higher in the obese versus lean subjects at all times, and decreased during recovery in both groups. In conclusion, abdominal subcutaneous adipose tissue responsiveness to beta-stimulation is not enhanced postexercise in lean and obese men, whereas previous exercise increases ATBF. Furthermore, the data suggest slower lipid mobilization postexercise and resistance to the antilipolytic effect of insulin in the obese.

Sjöstrand M, Gudbjörnsdottir S, Strindberg L, Lönnroth P. · Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital, S-41345 Göteborg, Sweden. · Diabetes. · Pubmed #15616023 links to  free full text

Abstract: Obese subjects exhibit a delay in insulin action and delivery of insulin to muscle interstitial fluid during glucose/insulin infusion. The aim of the present study was to follow the distribution of insulin to skeletal muscle after an oral glucose load in obese subjects. We conducted an oral glucose tolerance test (OGTT) in 10 lean and 10 obese subjects (BMI 23 +/- 0.6 vs. 33 +/- 1.2 kg/m(2); P < 0.001). Insulin measurements in muscle interstitial fluid were combined with forearm arteriovenous catheterization and blood flow measurements. In the obese group, interstitial insulin was significantly (35-55%) lower than plasma insulin (P < 0.05) during the 1st h after the OGTT, whereas in lean subjects, no significant difference was found between interstitial and plasma insulin levels during the same time period. The permeability surface area product for glucose, representing capillary recruitment, increased in the lean group (P < 0.05) but not in the obese group (NS). Obese subjects had a significantly higher plasma insulin level at 90-120 min after oral glucose (398 +/- 57 vs. 224 +/- 37 pmol/l in control subjects; P < 0.05). The significant gradient between plasma insulin and muscle interstitial insulin during the first hour after OGTT suggests a slow delivery of insulin in obese subjects. The hindered transcapillary transport of insulin may be attributable to a defect in insulin-mediated capillary recruitment.