Erik Näslund

Dynamics of fat cell turnover in humans

Obesity is increasing in an epidemic manner in most countries and constitutes a public health problem by enhancing the risk for cardiovascular disease and metabolic disorders such as type 2 diabetes. Owing to the increase in obesity, life expectancy may start to decrease in developed countries for the first time in recent history. The factors determining fat mass in adult humans are not fully understood, but increased lipid storage in already developed fat cells (adipocytes) is thought to be most important. Here we show that adipocyte number is a major determinant for the fat mass in adults. However, the number of fat cells stays constant in adulthood in lean and obese individuals, even after marked weight loss, indicating that the number of adipocytes is set during childhood and adolescence. To establish the dynamics within the stable population of adipocytes in adults, we have measured adipocyte turnover by analysing the integration of 14C derived from nuclear bomb tests in genomic DNA. Approximately 10% of fat cells are renewed annually at all adult ages and levels of body mass index. Neither adipocyte death nor generation rate is altered in early onset obesity, suggesting a tight regulation of fat cell number in this condition during adulthood. The high turnover of adipocytes establishes a new therapeutic target for pharmacological intervention in obesity.

Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men

BACKGROUND: Peripheral administration of glucagon-like peptide-1 (GLP-1) for four hours, to normal weight and obese humans, decreases food intake and suppresses appetite.OBJECTIVE: The aim of this study was to assess the effect of an eight hour infusion of GLP-1 on appetite and energy intake at lunch and dinner in obese subjects.DESIGN: Randomised, blinded cross-over design with intravenous infusion of GLP-1 (0.75 pmol·kg−1·min−1) or saline.SUBJECTS: Eight obese (body mass index, BMI, 45.5±2.3 kg/m2) male subjects.MEASUREMENTS: Ad libitum energy intake at lunch (12.00 h) and dinner (16.00 h) after an energy fixed breakfast (2.4 MJ) at 08.00 h. Appetite sensations using visual analogue scales, (VAS) immediately before and after meals and hourly in-between. Blood samples for the analysis of glucose, insulin, C-peptide, GLP-1 and peptide YY. Gastric emptying after breakfast and lunch using a paracetamol absorption technique.RESULTS: Hunger ratings were significantly lower with GLP-1 infusion. The summed ad libitum energy intake at lunch and dinner was reduced by 1.7±0.5 MJ (21±6%) by GLP-1 infusion (P=0.01). Gastric emptying was delayed by GLP-1 infusion, and plasma glucose concentrations decreased (baseline: 6.6±0.35 mmol/L; nadir: 5.3±0.15 mmol/L). No nausea was recorded during GLP-1 infusion.CONCLUSIONS: Our results demonstrate that GLP-1 decreases feelings of hunger and reduces energy intake in obese humans. One possible mechanism for this finding might be an increased satiety primarily mediated by gastric vagal afferent signals.

GLP-1 slows solid gastric emptying and inhibits insulin, glucagon, and PYY release in humans.

The aim of the present study was to assess the effect of glucagon-like peptide-1 (GLP-1) on solid gastric emptying and the subsequent release of pancreatic and intestinal hormones. In eight men [age 33.6 +/- 2.5 yr, body mass index 24.1 +/- 0.9 (means +/- SE)], scintigraphic solid gastric emptying during infusion of GLP-1 (0.75 pmol. kg(-1). min(-1)) or saline was studied for 180 min. Concomitantly, plasma concentrations of C- and N-terminal GLP-1, glucose, insulin, C-peptide, glucagon, and peptide YY (PYY) were assessed. Infusion of GLP-1 resulted in a profound inhibition of both the lag phase (GLP-1: 91.5, range 73.3-103.6 min vs. saline: 19. 5, range 10.2-43.4 min) and emptying rate (GLP-1: 0.34, range 0.06-0. 56 %/min vs. saline: 0.84, range 0.54-1.33 %/min; P < 0.01 for both) of solid gastric emptying. Concentrations of both intact and total GLP-1 were elevated to supraphysiological levels. Plasma glucose and glucagon concentrations were below baseline during infusion of GLP-1 in contrast to saline infusion, where concentrations were elevated above baseline (both P < 0.001). The insulin and C-peptide responses were lower during infusion with GLP-1 than with saline (P < 0.004 and P < 0.001, respectively). Plasma PYY concentrations decreased below baseline during GLP-1 infusion in contrast to saline, where concentrations were elevated above baseline (P = 0.04). Infusion of GLP-1 inhibits solid gastric emptying with secondary effects on the release of insulin, C-peptide, and glucagon, resulting in lower plasma glucose concentrations. In addition, the release of PYY into the circulation is inhibited by GLP-1 infusion, suggesting a negative feedback of GLP-1 on the function of the L-cell.

Changes in Glucose Homeostasis after Roux-en-Y Gastric Bypass Surgery for Obesity at Day Three, Two Months, and One Year after Surgery: Role of Gut Peptides

CONTEXT Endocrine effects of gastric bypass (GBP) surgery for obesity on glucose homeostasis are not fully understood. MAIN OBJECTIVE The main objective of the study was to assess the changes in plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), leptin, somatostatin, glucose-dependent insulinotropic peptide, enteroglucagon, and glucagon early after GBP. METHOD Twelve obese subjects (body mass index 45.3 ± 1.9 kg/m(2)) were subjected to a liquid meal without lipids before and 3 d, 2 months, and 1 yr after GBP. Plasma concentrations of glucose, insulin, leptin, and gut peptide hormones were assessed before and for 180 min after the meal. Satiety was measured with visual analog scales. The absorption rate of acetaminophen added to the liquid meal was measured. Insulin resistance was measured by the homeostasis model assessment of insulin resistance. RESULTS All subjects lost weight (body mass index 30.3 ± 1.8 kg/m(2) at 1 yr). Fasting glucose was significantly lower on d 3 (P < 0.05). There was a progressive decrease in the homeostasis model assessment of insulin resistance after 2 months postoperatively. Postprandially, there was a progressive rise of GLP-1 and enteroglucagon and a transient increase in pancreatic glucagon release over the study period. There was a leftward shift of the time course of plasma glucose and insulin. Somatostatin release was lower on d 3 (P < 0.05) but then unchanged. The absorption rate of acetaminophen was twice as fast after GBP compared with before surgery and did not change over time. Satiety scores increased markedly postoperatively. CONCLUSION Both enhanced insulin sensitivity and incretin hormones, such as GLP-1, contribute to the early control of glucose homeostasis. Progressively increasing postprandial levels of enteroglucagon (oxyntomodulin) and GLP-1 facilitate weight loss and enhance insulin effectiveness.

Gastrointestinal hormones and gastric emptying 20 years after jejunoileal bypass for massive obesity

OBJECTIVE: Some studies have shown a more rapid gastric emptying in obese subjects. Six to twelve months after jejunoileal bypass (JIB) neurotensin (NT) and enteroglucagon have been shown to be elevated after food intake. These hormones, together with peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) have been implicated in the reduction of upper gastrointestinal motility seen after infusion of nutrients into the ileum. AIM: To study if the postprandial gut hormone pattern and gastric emptying is altered 20 y after JIB. SUBJECTS: Seven subjects operated with JIB a mean (s.d.) 20±3 y ago, with a BMI of 44±4 kg/m2; at the time of surgery and 31±4 at present. For comparison seven sex-matched non-operated obese controls (BMI 43±3) were studied. METHODS: Serial blood samples were obtained every 10 min after intake of a 280 kcal meal. Radioimmunoassays for motilin, cholecystokinin (CCK), NT, PYY and GLP-1 were performed. Gastric emptying of a solid meal was studied using a radioactively labelled omelette (of 310 kcal) for 120 min). RESULTS: After JIB postprandial motilin, CCK, NT, PYY and GLP-1 were elevated compared to non-operated obese subjects. Similarly, basal levels of CCK, motilin, GLP-1 and PYY were elevated in the operated group. No difference was observed in the rate of gastric emptying between the two groups. CONCLUSION: Both fasting and postprandial gut hormone levels are elevated 20 y after JIB. The impact of long-term rapid stimulation of the ileum and subsequent raised gut hormone levels on gastric emptying is not clear.

Nationwide cohort study of post-gastric bypass hypoglycaemia including 5,040 patients undergoing surgery for obesity in 1986–2006 in Sweden

Aims/hypothesisSymptomatic hypoglycaemia with related confusion, syncope, epilepsy or seizures is a newly recognised complication of gastric bypass surgery for obesity. The incidence of these conditions is not known. We therefore studied the incidence of post-gastric bypass hypoglycaemia and related symptoms in patients who have undergone gastric bypass and a reference cohort from the general population of Sweden.MethodsThis is a nationwide cohort study based on national registries with 5,040 persons who underwent gastric bypass, vertical banded gastroplasty or gastric banding for obesity in Sweden between 1 January 1986 and 31 December 2006 and a cohort of ten referents per patient matched for sex and age randomly sampled from the general population. The incidence rates of hospitalisation for hypoglycaemia, confusion, syncope, epilepsy or seizures before and after dates of surgery or inclusion in the reference cohort were studied.ResultsPreoperative incidences of hospitalisation for hypoglycaemia were similar in the surgical and referent cohorts. After gastric bypass surgery, the adjusted hazard ratios were significantly elevated for hypoglycaemia (2.7 [95% CI 1.2–6.3]), confusion (2.8 [1.3–6.0]), syncope (4.9 [3.4–7.0]), epilepsy (3.0 [2.1–4.3]) and seizures (7.3 [5.0–10.8]). The proportions of gastric bypass patients and reference participants affected by hypoglycaemia were very low (0.2% and 0.04%, respectively). There was no increased risk of hypoglycaemia after vertical banded gastroplasty or gastric banding compared with the referent population.Conclusions/interpretationObese persons who have undergone gastric bypass have an increased risk of hospitalisation for diagnoses associated with post-gastric bypass hypoglycaemia, although few patients are affected.

Appetite signaling: from gut peptides and enteric nerves to brain.

The signaling systems underlying eating behavior control are complex. The current review focuses on gastrointestinal (GI) signaling systems as physiological key functions for metabolic control. Many of the peptides that are involved in the regulation of food intake in the brain are also found in the enteric nervous system and enteroendocrine cells of the mucosa of the GI tract. The only identified hunger-driving signal from the GI tract is ghrelin, which is mainly found in the mucosa of the stomach. Neuropeptides in the brain that influence food intake, of which neuropeptide Y, agouti gene-related peptide and orexins are stimulatory, while melanocortins and alpha-melanocortin stimulating hormone are inhibitory, are influenced by peptide signaling from the gut. These effects may take place directly through action of gut peptide in the brain or through nervous signaling from the periphery to the brain. The criteria for considering a gut hormone or neurotransmitter in a satiety signal seem to be fulfilled for cholecystokinin, glucagon-like peptide-1 and peptide YY(3-36). Other endogenous gut signals do not fulfill these criteria as they do not increase food intake in knock-out animals or in response to receptor antagonism, or display an inconsistent temporal profile with satiety and termination of the meal. Satiety signals from the GI tract act through the arcuate nucleus of the hypothalamus and the solitary tract nucleus of the brain stem, where neuronal networks directly linked to hypothalamic centers for food intake and eating behavior are activated. We have primarily focused on GI effects of various gut peptides involved in the regulation of food intake, using motor activity as a biomarker for the understanding of gut peptide effects promoting satiety.

Importance of Small Bowel Peptides for the Improved Glucose Metabolism 20 Years after Jejunoileal Bypass for Obesity

Background: Obese patients operated with jejunoileal bypass (JIB) have reduced plasma concentrations of insulin and glucose. Gastric inhibitory peptide/glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) have been found to have a profound incretin effect in humans. The aim of the present study was to examine the long-term effect of JIB on glucose metabolism. Methods: Four groups (lean, nonoperated obese, obese 9 months after JIB and obese 20 years after JIB) of six females each were given a mixed meal (280 kcal). Plasma samples were obtained every 10 min for 60 min postprandially and were analyzed for glucose, insulin, GIP and GLP-1. Results: A reduction in body mass index (kg/m2) was seen for the two patient groups operated with JIB (12.1, at 9 months post-op; 13.1, at 20 years post-op). Surgery by JIB resulted in a reduction of glucose and insulin values. Concomitantly there was an elevation of postprandial GIP and GLP-1 plasma concentrations. In the obese subjects 20 years after JIB both fasting and postprandial GIP and GLP-1 values were markedly elevated compared with the other three groups; and plasma glucose and insulin concentrations were maintained at normal levels. Conclusions: The improvement in glucose metabolism seen after JIB may be due to reduced insulin resistance after weight loss and/or increased levels of the incretin hormones GIP and GLP-1. Progressively, elevated levels of GIP and GLP-1 seem to be necessary to maintain glucose homeostasis at longterm follow-up after this procedure.

Surgical treatment of obesity

Obesity is very prevalent. Most treatments fail owing to hard-wired survival mechanisms, linking stress and appetite, which have become grossly maladaptive in the industrial era. Antiobesity (bariatric) surgery is a seemingly drastic, efficacious therapy for this serious disease of energy surfeit. Technical progress during the last two decades has greatly improved its safety. The surgical principles of gastric restriction and/or gastrointestinal diversion have remained largely unchanged over 40 years, although mechanisms of action have been elucidated concomitant with advances in knowledge of the molecular biology of energy balance and appetite regulation. Results of bariatric surgery in large case-series followed for at least 10 years consistently demonstrate amelioration of components of the insulin-resistance metabolic syndrome and other comorbidities, significantly improving quality of life. Furthermore, bariatric surgery has convincingly been demonstrated to reduce mortality compared with nonoperative methods. This surgery requires substantial preoperative and postoperative evaluation, teaching, and monitoring to optimize outcomes. In the absence of effective societal changes to restore a healthy energy balance, bariatric surgery is an important tool for treating a very serious disease.

Downregulation of Electron Transport Chain Genes in Visceral Adipose Tissue in Type 2 Diabetes Independent of Obesity and Possibly Involving Tumor Necrosis Factor-α

Impaired oxidative phosphorylation is suggested as a factor behind insulin resistance of skeletal muscle in type 2 diabetes. The role of oxidative phosphorylation in adipose tissue was elucidated from results of Affymetrix gene profiling in subcutaneous and visceral adipose tissue of eight nonobese healthy, eight obese healthy, and eight obese type 2 diabetic women. Downregulation of several genes in the electron transport chain was the most prominent finding in visceral fat of type 2 diabetic women independent of obesity, but the gene pattern was distinct from that previously reported in skeletal muscle in type 2 diabetes. A similar but much weaker effect was observed in subcutaneous fat. Tumor necrosis factor-α (TNF-α) is a major factor behind inflammation and insulin resistance in adipose tissue. TNF-α treatment decreased mRNA expression of electron transport chain genes and also inhibited fatty acid oxidation when differentiated human preadipocytes were treated with the cytokine for 48 h. Thus, type 2 diabetes is associated with a tissue- and region-specific downregulation of oxidative phosphorylation genes that is independent of obesity and at least in part mediated by TNF-α, suggesting that impaired oxidative phosphorylation of visceral adipose tissue has pathogenic importance for development of type 2 diabetes.