Amylin improves the effect of leptin on insulin sensitivity in leptin-resistant diet-induced obese mice

Abstract

improves the effect of leptin on insulin sensitivity in leptin-resistant diet-induced obese mice. Am J Physiol Endocrinol Metab 302: E924 -E931, 2012. First published January 24, 2012; doi:10.1152/ajpendo.00198.2011.-Leptin enhances insulin sensitivity in addition to reducing food intake and body weight. Recently, amylin, a pancreatic ␤-cell-derived hormone, was shown to restore a weight-reducing effect of leptin in leptin-resistant dietinduced obesity. However, whether amylin improves the effect of leptin on insulin sensitivity in diet-induced obesity is unclear. Dietinduced obese (DIO) mice were infused with either saline (S), leptin (L; 500 g·kg Ϫ1 ·day Ϫ1 ), amylin (A; 100 g·kg Ϫ1 ·day Ϫ1 ), or leptin plus amylin (L/A) for 14 days using osmotic minipumps. Food intake, body weight, metabolic parameters, tissue triglyceride content, and AMP-activated protein kinase (AMPK) activity were examined. Pairfeeding and weight-matched calorie restriction experiments were performed to assess the influence of food intake and body weight reduction. Continuous L/A coadministration significantly reduced food intake, increased energy expenditure, and reduced body weight, whereas administration of L or A alone had no effects. L/A coadministration did not affect blood glucose levels during ad libitum feeding but decreased plasma insulin levels significantly (by 48%), suggesting the enhancement of insulin sensitivity. Insulin tolerance test actually showed the increased effect of insulin in L/A-treated mice. In addition, L/A coadministration significantly decreased tissue triglyceride content and increased AMPK␣2 activity in skeletal muscle (by 67%). L/A coadministration enhanced insulin sensitivity more than pairfeeding and weight-matched calorie restriction. In conclusion, this study demonstrates the beneficial effect of L/A coadministration on glucose and lipid metabolism in DIO mice, indicating the possible clinical usefulness of L/A coadministration as a new antidiabetic treatment in obesity-associated diabetes. obesity; diabetes; adenosine 5=-monophosphate-activated protein kinase LEPTIN, AN ADIPOCYTE-DERIVED HORMONE, has a weight-reducing effect accompanied by reduction in food intake and increase in energy expenditure (11,13). In general, in rodent models of diet-induced obesity and obese human, although leptin levels rise proportionally with adiposity (16, 23), the increased leptin fails to suppress the progression of obesity. Moreover, even high pharmacological doses of leptin have demonstrated only marginal, if any, effects on body weight in diet-induced obese (DIO) rodents and obese humans (8,15). This leptin ineffectiveness is called leptin resistance.Recently, it was shown that amylin, a pancreatic ␤-cellderived hormone (4), restored a weight-reducing effect of leptin and that leptin/amylin coadministration effectively reduced body weight in DIO rats (34). Moreover, in overweight/ obese humans, coadministration of the amylin analog pramlintide and the leptin analog metreleptin induced significantly greater weight ...

Combinatorial gene construct and non-viral delivery for anti-obesity in diet-induced obese mice

“…s5). Interestingly, lPEI-pcDNA3-IAPP polyplex also exhibited a greater reduction in both body weight and food intake, when compared to no treatment, lPEI-pcDNA3, or lPEI-pcDNA3-LEP treatment, which is consistent with the previous reports [8,9,33]. Additionally, the lPEI-pcDNA3-LEP group did not show a sharp dip in either weight or food intake due to the intrinsic LEP resistance in DIO mice [9,12].…”

Serum Amylin Indicates Hypertriglyceridemia in Pre-diabetics

“…Consequently, given that insulin and amylin levels positively correlate (data not shown), our findings would suggest that elevated circulating amylin levels may be related to the increased insulin secretion observed as a compensation for decreased insulin action; however, the exact form of amylin (reduced, unreduced, or amylin acid) which could be responsible remains elusive. Consistent with our proposal, amylin can act as a neuroendocrine hormone that complements the effects of insulin in postprandial regulation and there is evidence that in mice amylin improves leptin-mediated increases in insulin sensitivity [25]. As seen with our results, the unreduced (biological active) form failed to correlate with hypertriglyceridemia, indicating the mechanisms by which elevated levels of amylin may affect insulin action are unknown.…”

KBP-042 improves bodyweight and glucose homeostasis with indices of increased insulin sensitivity irrespective of route of administration

“…The resistance towards leptin in this study was confirmed in a food intake test where leptin alone did not alter the food intake in HFD rats. This resistance to leptin was ameliorated by the treatment with KBP-042 as is also known from amylin treatment (Kusakabe et al, 2012). KBP-042 lowers food intake alone, however a clear potentiating effect was seen when the combination of the two peptides was given, and the lowered plasma levels of leptin also supports this.…”