Andreas Lindqvist

High-fat diet impairs hippocampal neurogenesis in male rats.

High fat diets and obesity pose serious health problems, such as type II diabetes and cardiovascular disease. Impaired cognitive function is also associated with high fat intake. In this study, we show that just 4 weeks of feeding a diet rich in fat ad libitum decreased hippocampal neurogenesis in male, but not female, rats. There was no obesity, but male rats fed a diet rich in fat exhibited elevated serum corticosterone levels compared with those fed standard rat chow. These data indicate that high dietary fat intake can disrupt hippocampal neurogenesis, probably through an increase in serum corticosterone levels, and that males are more susceptible than females.

Effects of sucrose, glucose and fructose on peripheral and central appetite signals.

In the Western world, consumption of soft drinks has increased the last three decades and is partly responsible for the epidemic-like increase in obesity. Soft drinks, originally sweetened by sucrose, are now sweetened by other caloric sweeteners, such as fructose. In this study, we investigated the short-term effect of sucrose, glucose or fructose solutions on food intake and body weight in rats, and on peripheral and central appetite signals. Rats received water containing either of the sugars and standard rat chow for two weeks. Rats receiving water alone and standard chow were controls. All rats offered the sugar solutions increased their total caloric intake. The increased caloric intake occurred despite the fact that the rats offered either of the sugar solutions consumed less chow. As a consequence of the increased caloric intake, the sugar-drinking rats had elevated serum levels of free fatty acids, triglycerides and cholesterol. In addition, consuming sugar solutions resulted in increased serum leptin, decreased serum PYY and down-regulated hypothalamic NPY mRNA. Serum ghrelin was increased in rats receiving fructose solution. Moreover, consumption of sucrose or fructose solution resulted in up-regulated hypothalamic CB1 mRNA. Hypothalamic POMC mRNA was down-regulated in rats receiving glucose or fructose. In conclusion, consumption of glucose, sucrose or fructose solution results in caloric overconsumption and body weight gain through activation of hunger signals and depression of satiety signals as well as activation of reward components. The weight-promoting effect of these sugar solutions may possibly be ameliorated by the down-regulation of NPY mRNA and increased serum leptin.

Ghrelin treatment reverses the reduction in weight gain and body fat in gastrectomised mice.

Background and aims: The gastric hormone ghrelin has been reported to stimulate food intake, increase weight gain, and cause obesity but its precise physiological role remains unclear. We investigated the long term effects of gastrectomy evoked ghrelin deficiency and of daily ghrelin injections on daily food intake, body weight, fat mass, lean body mass, and bone mass in mice. Methods: Ghrelin was given by subcutaneous injections (12 nmol/mouse once daily) for eight weeks to young female mice subjected to gastrectomy or sham operation one week previously. Results: Gastrectomy reduced plasma concentrations of total ghrelin (octanoylated and des-octanoylated) and active (octanoylated) ghrelin by ∼80%. Immediately after injection of ghrelin, the plasma concentration was supraphysiological and was still elevated 16 hours later. Daily food intake was not affected by either gastrectomy or ghrelin treatment. The effect of ghrelin on meal initiation was not studied. At the end point of the study, mean body weight was 15% lower in gastrectomised mice than in sham operated mice (p<0.001); daily ghrelin injections for eight weeks partially prevented this weight loss. In sham operated mice, ghrelin had no effect on body weight. The weight of fat was reduced in gastrectomised mice (−30%; p<0.01). This effect was reversed by ghrelin, enhancing the weight of fat in sham operated mice also (+20%; p<0.05). Gastrectomy reduced lean body mass (−10%; p<0.01) and bone mass (−20%; p<0.001) compared with sham operated mice. Ghrelin replacement prevented the gastrectomy induced decrease in lean body mass but did not affect bone. In sham operated mice, ghrelin affected neither of these two parameters. Conclusions: Ghrelin replacement partially reversed the gastrectomy induced reduction in body weight, lean body mass, and body fat but not in bone mass. In sham operated mice, ghrelin only increased fat mass. Our results suggest that ghrelin is mainly concerned with the control of fat metabolism and that ghrelin replacement therapy may alleviate the weight loss associated with gastrectomy.

Overeating of palatable food is associated with blunted leptin and ghrelin responses.

Palatable food is rich in fat and/or sucrose. In this study we examined the long-term effects of such diets on food intake, body weight, adiposity and circulating levels of the satiety peptide leptin and the hunger peptide ghrelin. The experiments involved rats and mice and lasted 5 weeks. In rats, we examined the effect of diets rich in fat and/or sucrose and in mice the effect of a high fat diet with or without sucrose in the drinking water. Animals fed with the palatable diets had a larger intake of calories, gained more weight and became more adipose than animals fed standard rat chow. Fasted animals are known to have low serum leptin and high serum ghrelin and to display elevated serum leptin and lowered serum ghrelin postprandially. With time, a sucrose-rich diet was found to raise the fasting level of leptin and to lower the fasting level of ghrelin in rats. A fat-rich diet suppressed serum ghrelin without affecting serum leptin; high sucrose and high fat in combination greatly reduced serum ghrelin and raised serum leptin in the fasted state. The mRNA expression of leptin in the rat stomach was up-regulated by sucrose-rich (but not by fat-rich) diets, whereas the expression of ghrelin seemed not to be affected by the palatable diets. Mice responded to sucrose in the drinking water with elevated serum leptin (fasted state) and to all palatable diets with low serum ghrelin. The expression of both leptin and ghrelin mRNA in the stomach was suppressed in fasted mice that had received a high fat diet for 5 weeks. We conclude that the expression of leptin mRNA in stomach and the concentration of leptin in serum were elevated in response to sucrose-rich rather than fat-rich diets, linking leptin with sucrose metabolism. In contrast, the expression of ghrelin and the serum ghrelin concentration were suppressed by all palatable diets, sucrose and fat alike. In view of the increased body weight and adiposity neither elevated leptin nor suppressed ghrelin were able to control/restrain the overeating that is associated with palatable diets.

Reduced neurogenesis in the rat hippocampus following high fructose consumption.

In this study, we investigated how prolonged consumption of sugar solution affects hippocampal neurogenesis. We gave rats sucrose or fructose solution for four weeks and observed a 40% reduction in BrdU/NeuN-immunoreactive cells in the hippocampal dentate gyrus. This reduction in hippocampal neurogenesis was accompanied by increased apoptosis in the hippocampus and increased circulating levels of TNF-α. Therefore, we hypothesize that the reduction in hippocampal neurogenesis may be due to the increased apoptosis induced by TNF-α. Our results suggest that chronic ingestion of fructose is detrimental to the survival of newborn hippocampal neurones. The results presented in the present study add to the list of harmful effects associated with prolonged and excessive consumption of sugary beverages and soft drinks.

Thylakoids promote release of the satiety hormone cholecystokinin while reducing insulin in healthy humans

Objective. The effects of a promising new appetite suppressor named “thylakoids” (membrane proteins derived from spinach leaves) were examined in a single meal in man. Thylakoids inhibit the lipase/colipase hydrolysis of triacylglycerols in vitro and suppress food intake, decrease body-weight gain and raise the satiety hormone cholecystokinin (CCK) in rats, but their effects in man remain unclear. The aim of this study was to investigate whether thylakoids, when added to a test meal, affect appetite regulation and blood parameters in healthy individuals. Material and methods. In an intervention crossover study, healthy individuals of normal weight (n=11) were offered a high-fat meal with and without the addition of thylakoids. Blood samples were taken 0 (prior to meal), 30, 60, 120, 180, 240, 300 and 360 min after the start of the meal. Blood samples were analysed for satiety and hunger hormones (CCK, leptin and ghrelin), insulin and blood metabolites (glucose and free fatty acids). Results. The CCK level increased, in particular between the 120 min time-point and onwards, the ghrelin level was reduced at 120 min and leptin level increased at 360 min after intake of the thylakoid-enriched meal. The insulin level was reduced, whereas glucose concentrations were unchanged. Free fatty acids were reduced between time-point 120 min and onwards after the thylakoid meal. Conclusions. The addition of thylakoids to energy-dense food promotes satiety signals and reduces insulin response during a single meal in man.

Nesfatin-1 stimulates glucagon and insulin secretion and beta cell NUCB2 is reduced in human type 2 diabetic subjects.

Nesfatin-1 is a novel anorexigenic regulatory peptide. The peptide is the N-terminal part of nucleobindin 2 (NUCB2) and is expressed in brain areas regulating feeding. Outside the brain, nesfatin-1 expression has been reported in adipocytes, gastric endocrine cells and islet cells. We studied NUCB2 expression in human and rodent islets using immunocytochemistry, in situ hybridization and western blot. Furthermore, we investigated the potential influence of nesfatin-1 on secretion of insulin and glucagon in vitro and in vivo in mice and in INS-1 (832/13) cells. The impact of type 2 diabetes (T2D) and glucolipotoxicity on NUCB2 gene expression in human islets and its relationship to insulin secretory capacity and islet gene expression was studied using microarray. Nesfatin-1 immunoreactivity (IR) was abundant in human and rodent beta cells but absent in alpha, delta, PP and ghrelin cells. Importantly, in situ hybridization showed that NUCB2 mRNA is expressed in human and rat islets. Western blot analysis showed that nesfatin-1 IR represented full length NUCB2 in rodent islets. Human islet NUCB2 mRNA was reduced in T2D subjects but upregulated after culture in glucolipotoxic conditions. Furthermore, a positive correlation between NUCB2 and glucagon and insulin gene expression, as well as insulin secretory capacity, was evident. Nesfatin-1 enhanced glucagon secretion but had no effect on insulin secretion from mouse islets or INS-1 (832/13) cells. On the other hand, nesfatin-1 caused a small increase in insulin secretion and reduced glucose during IVGTT in mice. We conclude that nesfatin-1 is a novel glucagon-stimulatory peptide expressed in the beta cell and that its expression is decreased in T2D islets.

Gastric bypass improves ss-cell function and increases β-cell mass in a porcine model.

The most frequently used and effective treatment for morbid obesity is Roux-en-Y gastric bypass surgery (RYGB), which results in rapid remission of type 2 diabetes in most cases. To what extent this is accounted for by weight loss or other factors remains elusive. To gain insight into these mechanisms, we investigated the effects of RYGB on β-cell function and β-cell mass in the pig, a species highly reminiscent of the human. RYGB was performed using linear staplers during open surgery. Sham-operated pigs were used as controls. Both groups were fed a low-calorie diet for 3 weeks after surgery. Intravenous glucose tolerance tests were performed 2 weeks after surgery. Body weight in RYGB pigs and sham-operated, pair-fed control pigs developed similarly. RYGB pigs displayed improved glycemic control, which was attributed to increases in β-cell mass, islet number, and number of extraislet β-cells. Pancreatic expression of insulin and glucagon was elevated, and cells expressing the glucagon-like peptide 1 receptor were more abundant in RYGB pigs. Our data from a pig model of RYGB emphasize the key role of improved β-cell function and β-cell mass to explain the improved glucose tolerance after RYGB as food intake and body weight remained identical.

Thylakoids suppress appetite by increasing cholecystokinin resulting in lower food intake and body weight in high-fat fed mice

Thylakoids are membranes isolated from plant chloroplasts which have previously been shown to inhibit pancreatic lipase/colipase catalysed hydrolysis of fat in vitro and induce short‐term satiety in vivo. The purpose of the present study was to examine if dietary supplementation of thylakoids could affect food intake and body weight during long‐term feeding in mice. Female apolipoprotein E‐deficient mice were fed a high‐fat diet containing 41% of fat by energy with and without thylakoids for 100 days. Mice fed the thylakoid‐enriched diet had suppressed food intake, body weight gain and body fat compared with the high‐fat fed control mice. Reduced serum glucose, serum triglyceride and serum free fatty acid levels were found in the thylakoid‐treated animals. The satiety hormone cholecystokinin was elevated, suggesting this hormone mediates satiety. Leptin levels were reduced, reflecting a decreased fat mass. There was no sign of desensitization in the animals treated with thylakoids. The results suggest that thylakoids are useful to suppress appetite and body weight gain when supplemented to a high‐fat food during long‐term feeding. Copyright

Effects of ingestion routes on hormonal and metabolic profiles in gastric-bypassed humans

CONTEXT Gastric bypass surgery (GBP) results in the rapid resolution of type 2 diabetes. Most studies aiming to explain the underlying mechanisms are limited to data obtained after a postsurgical recovery period, making assessment of confounding influences from, for example, weight loss and altered nutrient intake difficult. OBJECTIVE To examine the impact of GBP on hormonal and metabolite profiles under conditions of identical nutrient intake independent of weight loss, we studied GBP patients fitted with a gastrostomy tube to enable the administration of nutrients to bypassed segments of the gut. Thus, this model allowed us to simulate partially the preoperative condition and compare this with the postoperative situation in the same patient. DESIGN Patients (n = 4) were first given a mixed meal test (MMT) orally and then via the gastrostomy tube, preceded by overnight and 2-hour fasting, respectively. Blood samples were assessed for hormones and metabolites. RESULTS The oral MMT yielded 4.6-fold increase in plasma insulin (P < .05), 2-fold in glucagon-like peptide-1 (P < .05), and 2.5-fold in glucose-dependent insulinotropic peptide (P < .05) plasma levels, compared with the gastrostomy MMT. The changes in hormone levels were accompanied by elevated branched-chain amino acid levels (1.4-2-fold, P < .05) and suppressed fatty acid levels (∼50%, P < .05). CONCLUSIONS These data, comparing identical nutrient delivery, demonstrate markedly higher incretin and insulin responses after oral MMT than after gastric MMT, thereby providing a potential explanation for the rapid remission of type 2 diabetes observed after GBP. The simultaneous increase in branched-chain amino acid questions its role as a marker for insulin resistance.