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Leptin and glucose homeostasis

Leptin required for glucose homeostasis after RYGB

Leptin is required for the effect of RYGB to improve glucose tolerance and insulin sensitivity

A study in mice has found that leptin is required for the effects of Roux-en-Y Gastric Bypass (RYGB) on glucose homeostasis but not body weight or composition in mice, suggesting that leptin may play a role in post-RYGB weight maintenance. In their paper, ‘Leptin Is Required for Glucose Homeostasis after Roux-en-Y Gastric Bypass in Mice’, published online in PlosOne, the authors from Carver College of Medicine, University of Iowa, Iowa City, Iowa and UT Southwestern Medical Center, Dallas, TX, US, they add that leptin’s involvement in post-RYGB weight maintenance maybe related to an “increased dietary energy content and intake with resultant weight regain as can occur in patients late after surgery.”

The authors write that leptin is known to increase energy expenditure, reduce food intake, and regulate glucose homeostasis and hepatic insulin sensitivity via hypothalamic proopiomelanocortin neurons in mice. However, they wanted to assess whether leptin is required for sustained weight reduction and improved glucose homeostasis observed after RYGB as this could lead to the development of therapies that are less invasive and can be applied more safely and broadly than surgery. Therefore, they performed RYGB or sham operations in leptin-deficient ob/ob mice, which are severely obese, hyperinsulinemic, and insulin resistant and theorised that RYGB would fail to reduce body weight and improve glucose homeostasis in ob/ob mice.

At ten weeks of age, ob/ob mice were randomised to RYGB or sham operations and to avoid confounding of RYGB-induced changes in energy balance and body weight by peri-operative weight loss between animals and groups, all mice were weight-matched to the RYGB group via calorie restriction during week two.

Outcomes

The results revealed that both surgical groups lost weight due to the effects of intra-operative stress and peri-operative calorie restriction. After post-operative recovery and upon resumption of ad libitum at the end of post-operative week two, sham-operated animals gained 0.56±0.03g/day, reaching a total body weight of 52.7±0.8g by week six. Whereas the RYGB mice regained weight at a greatly reduced rate of 0.05±0.05g/day and reaching only 37.5±1.8g by week 6, a reduction of 29% compared to shams.

Expressed as a percentage of pre-operative weight, sham mice weighed 108.6±1.7% while RYGB mice weighed 75.8±3.6% for a difference of 33%, and RYGB reduced fat mass by 36% and lean mass by 13%. During week six, the total body weight of sham-treated ob/ob mice was equivalent to non-operated, age-matched ob/ob mice (52.7±0.8g, sham-treated ob/ob mice versus 55.3±0.6g, non-operated ob/ob mice, p>0.05) demonstrating complete recovery from their peri-operative weight loss.

The report that RYGB failed to improve glucose tolerance or reduce glucose-stimulated plasma insulin levels in ob/ob mice and the procedure also failed to improve insulin tolerance. However, these parameters were improved in DIO C57BL/6 mice after RYGB - suggesting that leptin is required for the effect of RYGB to improve peripheral insulin sensitivity.

In contrast, RYGB reduced fasting blood glucose compared to shams as fasting plasma insulin was increased after RYGB (while plasma glucagon was unchanged), demonstrate, the researchers claim, that the effect of RYGB to reduce fasting glucose is independent of changes in body weight and food intake as well as plasma leptin, insulin, and glucagon.

“In summary, we demonstrate that leptin is dispensable for the weight-reducing and anorectic effects of RYGB. However, leptin is required for the effect of RYGB to improve glucose tolerance and insulin sensitivity,” they conclude. “…These data further define the underlying mechanisms of the beneficial effects of RYGB on body weight and glucose homeostasis and may facilitate the development of alternate, less-invasive yet similarly efficacious therapies than bariatric surgery.”

To access this paper, please click here

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