BADERC- L. M. Kaplan

L. M. Kaplan, M.D., Ph.D.

Gastrointestinal Regulation of Metabolic Function

Dr. Kaplan’s research is focused on the regulation of metabolic function by the gastrointestinal tract. Over the past several years, his group has explored the mechanisms underlying the effects of various forms of GI weight loss surgery (bariatric surgery) on body weight, glucose homeostasis and other metabolic functions. Using newly developed rat and mouse models of several of these procedures, he has demonstrated that Roux-en-Y gastric bypass (RYGB) exerts its therapeutic effects by altering physiological regulatory processes rather than by mechanically interfering with food intake or inducing calorie malabsorption. These studies have demonstrated that RYGB induces weight loss in rats and mice both by decreasing food intake and increasing resting energy expenditure. Intact leptin signaling is required only for the effects on food intake, suggesting that RYGB modulates selective components of the endogenous weight regulatory apparatus. In contrast to RYGB, procedures that alter only the stomach (e.g., gastric banding and vertical sleeve gastrectomy) induce weight loss by altering food intake alone, suggesting that changes in energy expenditure after RYGB emanate from manipulation of the small intestine. With respect to GI regulation of glucose homeostasis, Dr. Kaplan’s group has found that RYGB exerts both weight loss-dependent and weight-independent effects. In diabetic rodents, changes in fasting glucose after RYGB appear related primarily to the weight loss associated with the surgery. In contrast, glucose tolerance and improvement in β-cell function result from the surgery itself, independent of weight loss. In thin, diabetic GK rats, RYGB induces β-cell hyperplasia and improved β-cell function. Like changes in energy expenditure, these effects appear to be mediated primarily by the intestinal component of this operation. Ongoing studies in the laboratory are aimed at combining pharmacological, genetic and surgical manipulation of mice to explore the cellular and molecular basis of these physiological effects. The ultimate goals of this work are to understand the mechanisms underlying these powerful, and durable, surgical manipulations, in order to (1) develop less invasive means of achieving the same clinical outcomes, and (2) increase understanding of the molecular mechanisms by which the GI tract helps regulate energy balance, glucose homeostasis and other metabolic functions.

References:

Stylopoulos N, Hoppin AG, Kaplan LM. Roux-en-Y gastric bypass enhances energy expenditure and extends lifespan in diet-induced obese rats. Obesity 2009; in press.
Hatoum IJ, Stein HK, Merrifield BF, Kaplan LM. Capacity for physical activity predicts weight loss after Roux-en-Y gastric bypass. Obesity 2009; 17:92-99.
Aguirre V, Stylopoulos N, Grinbaum R, Kaplan LM. An endoluminal sleeve induces substantial weight loss and normalizes glucose homeostasis in rats with diet-induced obesity. Obesity 2008; 16:2585-2592. epub 2008 October 30.
Kathiresan S, Willer CJ, Peloso G, Demissie S, Musunuru K, Schadt E, Kaplan LM, Clarke R, Li Y,Tanaka T, Voight B, Bonnycastle LL, Jackson AU, Crawford G, Surti A, Guiducci C, Burtt N, Parish S, Bennett D, Zelenika D, et al. Common DNA sequence variants at twenty-nine genetic loci contribute to polygenic dyslipidemia. Nat Genet 2008; 41:56-65.






			L. M. Kaplan, M.D., Ph.D. Gastrointestinal Regulation of Metabolic Function Dr. Kaplan’s research is focused on the regulation of metabolic function by the gastrointestinal tract. Over the past several years, his group has explored the mechanisms underlying the effects of various forms of GI weight loss surgery (bariatric surgery) on body weight, glucose homeostasis and other metabolic functions. Using newly developed rat and mouse models of several of these procedures, he has demonstrated that Roux-en-Y gastric bypass (RYGB) exerts its therapeutic effects by altering physiological regulatory processes rather than by mechanically interfering with food intake or inducing calorie malabsorption. These studies have demonstrated that RYGB induces weight loss in rats and mice both by decreasing food intake and increasing resting energy expenditure. Intact leptin signaling is required only for the effects on food intake, suggesting that RYGB modulates selective components of the endogenous weight regulatory apparatus. In contrast to RYGB, procedures that alter only the stomach (e.g., gastric banding and vertical sleeve gastrectomy) induce weight loss by altering food intake alone, suggesting that changes in energy expenditure after RYGB emanate from manipulation of the small intestine. With respect to GI regulation of glucose homeostasis, Dr. Kaplan’s group has found that RYGB exerts both weight loss-dependent and weight-independent effects. In diabetic rodents, changes in fasting glucose after RYGB appear related primarily to the weight loss associated with the surgery. In contrast, glucose tolerance and improvement in β-cell function result from the surgery itself, independent of weight loss. In thin, diabetic GK rats, RYGB induces β-cell hyperplasia and improved β-cell function. Like changes in energy expenditure, these effects appear to be mediated primarily by the intestinal component of this operation. Ongoing studies in the laboratory are aimed at combining pharmacological, genetic and surgical manipulation of mice to explore the cellular and molecular basis of these physiological effects. The ultimate goals of this work are to understand the mechanisms underlying these powerful, and durable, surgical manipulations, in order to (1) develop less invasive means of achieving the same clinical outcomes, and (2) increase understanding of the molecular mechanisms by which the GI tract helps regulate energy balance, glucose homeostasis and other metabolic functions. References: Stylopoulos N, Hoppin AG, Kaplan LM. Roux-en-Y gastric bypass enhances energy expenditure and extends lifespan in diet-induced obese rats. Obesity 2009; in press. Hatoum IJ, Stein HK, Merrifield BF, Kaplan LM. Capacity for physical activity predicts weight loss after Roux-en-Y gastric bypass. Obesity 2009; 17:92-99. Aguirre V, Stylopoulos N, Grinbaum R, Kaplan LM. An endoluminal sleeve induces substantial weight loss and normalizes glucose homeostasis in rats with diet-induced obesity. Obesity 2008; 16:2585-2592. epub 2008 October 30. Kathiresan S, Willer CJ, Peloso G, Demissie S, Musunuru K, Schadt E, Kaplan LM, Clarke R, Li Y,Tanaka T, Voight B, Bonnycastle LL, Jackson AU, Crawford G, Surti A, Guiducci C, Burtt N, Parish S, Bennett D, Zelenika D, et al. Common DNA sequence variants at twenty-nine genetic loci contribute to polygenic dyslipidemia. Nat Genet 2008; 41:56-65.