22 Sep Brain RAP is a Critical Mediator of Leptin Resistance and Obesity
Posted at 01:23h
in Author Interviews, Baylor College of Medicine Houston, Biomarkers, Weight Research
MedicalResearch.com Interview with:
[caption id="attachment_28232" align="alignleft" width="144"]
Dr. Makoto Fukuda[/caption]
Makoto Fukuda Ph.D.
Assistant Professor
Children's Nutrition Research Center
Department of Pediatrics
Baylor College of Medicine
Houston, Texas 77030
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: A hallmark characteristic of obesity is diminished actions of metabolic hormones that are critically required to maintain whole body energy balance and glucose homeostasis. Leptin is a crucial and powerful hormone that keeps body weight normal. It was hoped that leptin might be a “magic bullet” that could cure obesity. Shortly after the discovery, however, obese individuals were found to have little or no response to exogenously administered leptin, a state of “leptin resistance”. These observations created a central question to be addressed in the field, which would help our understanding of the core of pathophysiology of obesity. While we and other groups previously demonstrated that Epac, a signaling molecule known as a GTP/GDP exchange factor directly activated by cAMP, is involved in cellular leptin resistance, the role of brain Epac signaling in the whole body metabolism has not yet established.
We approached this question by using brain-specific knockout mice of Rap1, a direct activator of Epac. As expected from previous results, mice with brain-specific deficiency of Rap1 failed to develop leptin resistance even when they were challenged with a hypercaloric diet. What impressed us most in this study was that Rap1 in the brain plays a key role in the whole body metabolic control, beyond its role in controlling leptin sensitivity. Loss of brain Rap1 protects mice from diet-induced obesity and disordered glucose balance, whereas these knockout mice maintained a similar body weight to that of control mice on a normal regular diet. Further, pharmacological inhibition of this pathway reversed leptin resistance and reduced the body weight of dietary obese mice. At the cellular level, we found an unexpected link between Rap1 and endoplasmic reticulum (ER) stress that has emerged as a causative contributor to the development of leptin resistance.




















Dr. Annika Rosengren[/caption]
Annika Rosengren MD
Department of Molecular and Clinical Medicine, Institute of Medicine
Sahlgrenska Academy
University of Gothenburg,
Gothenburg, Sweden
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: In an earlier study we found that while hospitalizations for heart failure decreased among people aged 55 and older in Sweden 1987-2006, there was a clear increase among those younger than 45 years, particularly in young men. We thought that increasing body weight in the population might be a factor behind this.
We used anonymized data from more than 1.6 million Swedish men from the Swedish conscript registry aged on average 18 and followed them from adolescence onwards. Those who were overweight as teenagers were markedly more likely to develop heart failure in early middle age. The increased risk of heart failure was found already in men who were within the normal body weight range (a body mass index of 18.5 to 25) in adolescence, with an increased risk starting in those with a BMI of 20 and rising steeply to a nearly ten-fold increased risk in those who were very obese, with a BMI of 35 or over.
Among men with a BMI of 20 and over, the risk of heart failure increased by 16% with every BMI unit, after adjustments for factors that could affect the findings, such as age, year of enlistment into the Swedish armed forces, other diseases, parental education, blood pressure, IQ, muscle strength and fitness.
Dr. Mikhail Kolonin[/caption]
Mikhail Kolonin, PhD, Associate Professor
Director, Center for Metabolic and Degenerative Diseases
Harry E. Bovay, Jr. Distinguished University Chair in Metabolic Disease Research
The Brown Foundation Institute of Molecular Medicine
University of Texas Health Science Center at Houston
Houston, TX 77030
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Epidemiology studies have indicated that in obese patients progression of prostate, breast, colorectal, and other cancers is more aggressive. Adipose (fat) tissue, expanding and undergoing inflammation in obesity, directly fuels tumor growth. Adipose tissue is composed by adipocytes and stromal/vascular cells, which secrete tumor-trophic factors. Previous studies by our group have demonstrated that adipose stromal cells, which support blood vessels and serve as adipocyte progenitors, are recruited by tumors and contribute to cancer progression. Mechanisms underlying stromal cell trafficking from fat tissue to tumors have remained obscure. We discovered that in obesity a chemokine CXCL1, expressed by cancer cells, attracts adipose stromal cells to tumors.