Multi-faceted Evaluations Following Weight Reduction in Subjects With Metabolic Syndrome
Multi-faceted Evaluations Following Weight Reduction in Subjects With Metabolic Syndrome
Central obesity, core of metabolic syndrome, has been recognized as one of the rooting
 factors for development of diabetes and cardiovascular disease. Although efforts have been
 devoted to the studies of central obesity and/or metabolic syndrome, much remained unknown as
 to how obesity influences cellular as well as cardiac functions, what is the central
 regulation of one's body weight.

 Weight loss is an undisputed way to improve cardiovascular and metabolic disorders in obese
 individuals. Previous studies have demonstrated that weight loss by 5% of initial weight
 universally provide substantial benefits in these subjects. However, there are little
 integrated research teams, composed of different disciplines, share common weight reduction
 program to look at different aspects of weight reduction in non-diabetic individuals with
 metabolic syndrome. The significances of this proposal we plan to target, namely Rho kinase
 activity from peripheral leukocyte, several cardiac functions measured by noninvasive
 technique (VP-2000) and MRI, circulating brain-derived neurotrophic factors (BDNF) levels,
 are fully explained detailed in each sub-proposal.

 In order to accomplish this integrated proposal, we will form research teams including
 endocrinologists, cardiologists, radiologists, and a coordinating data center. We pan to
 recruit 40 non-diabetic individuals with metabolic syndrome to participate this 12-16 weeks
 weight reduction program. Twenty-five age, sex matched non-diabetes lean will be served as
 controls. Oral glucose tolerance test, fasting blood obtained, noninvasive vascular and MRI
 examinations will be applied before and after weight reduction program in those achieving at
 least 5% loss of initial weight.

 In summary, this study will investigate the effects of weight loss on (1) Rho kinase activity
 obtained from peripheral leukocyte; (2). Aortic stiffness, central aortic pressure and
 hemodynamic by a noninvasive vascular profiling system (VP-2000); (3) Brain function
 specifically reflecting by circulating BDNF; (4). Aortic elastic properties and left
 ventricular function by using MRI examinations, in non-diabetic individuals of metabolic
 syndrome.
Obesity, in particular central obesity, has been one of the important documented risk factors
 for development of diabetes and cardiovascular disease. Recent re-delineated various versions
 of definitions of metabolic syndrome, has fueled further the critical involvement of central
 adiposity in these disorders through several facets, including many increased circulating
 pro-inflammatory cytokines, directly or indirectly linking to visceral adipose tissue
 expressions. Although lots of efforts have been devoted to the studies of central obesity
 and/or metabolic syndrome, much remained unknown as to how obesity affect cellular as well as
 cardiac function, what is the central regulation of one's body weight, and how to measure fat
 in visceral organs precisely.

 Weight loss is an undisputed way to improve cardiovascular and metabolic disorders. Both a
 recent review article and data from us demonstrated that only weight loss by 5% of initial
 weight universally delivered benefits on obese individuals. However, there is little
 integrated research teams from different disciplines share common weight reduction protocol
 and look at different aspects of weight reduction in non-diabetic individuals with metabolic
 syndrome. The significances of this proposal we plan to target are explained in detail in
 each sub-proposal. However, we would like to make a briefing description here.

 1. . Rho kinase (ROCK) is a serine/threonine kinase that mediates the downstream signaling
 of the small guanosine triphosphate- binding protein, Rho, on the actin cytoskeleton. In
 mostly animal models, the inhibition of ROCK ameliorates many cardiovascular conditions,
 including hypertension, atherosclerosis, myocardial fibrosis, and stroke. Recent study
 from Taiwan showed that ROCK activity is increased in patients with metabolic syndrome.

 2. . Obese and overweight individuals have increased levels of arterial stiffness which is
 a measure of aortic and large vessel distensibility or compliance. Weight loss could
 induce significant reduction in sympathetic activity and blood pressure. However, little
 is known as whether weight loss can improve arterial stiffness, central aortic blood
 pressure and related hemodynamics.

 3. . Brain-derived neurotrophic factor (BDNF), recently reported related to Alzheimer's
 disease, is present in brain tissues extensively. It is also noted that low circulating
 level of BDNF was associated with impaired glucose metabolism, and might be associated
 higher BMI or body fat. We are interesting in effect of weight reduction on circulating
 BDNF values in non-diabetic subjects with metabolic syndrome.

 4. . Magnetic resonance imaging (MRI) of the heart is frequently used and can provide
 accurate and reproducible measurement of LV mass, volumes, systolic function and aortic
 pulse velocity. Although echo-cardiography has been applied to study effect of weight
 loss on cardiac function, there has been no study by using cardiac MRI to measure cine
 images of cardiac function and related variables before and after weight reduction in
 non-diabetic subjects with metabolic syndrome.

 In order to accomplish this integrated proposal, we will formulate research teams including
 endocrinologists, cardiologists, radiologists, and a data center, coordinated by a PhD
 researcher (infra-structure as described below). We will recruit 40 non-diabetic individuals
 with metabolic syndrome (fulfilled the criteria from IDF, 2006 and DOH of Taiwan).
 Twenty-five age, sex matched non-diabetes lean will be served as controls.

 Written informed consent will be obtained from each subject before being enrolled into the
 study after approval from IRB of Taichung VGH, Taichung, Taiwan. This weight reduction
 program will be assisted by experienced dieticians and sports experts, all of whom we had
 collaborated and published article previously. This program will last for 12-16 weeks with
 every participants join together courses 4 hours per week. Each participant will be
 introduced a dietary plan based on a caloric reduction of 1200 Kcal/day from the values
 thought necessary to maintain their usual weight. Subject will be asked to follow dietary
 advice and their eating habit will be reviewed by dietician at the time of their weekly
 visit. Activity levels will be encouraged to reach 30 min each day and at least 5 days a
 week. During each visit, weight of each participant will be recorded and announced. Meals
 replacement may considered for those did not get much improvement during weekly monitoring
 since recent report indicated that meals replacement may provide certain help in reducing
 body weight. We are confident that adequate weight reduction (at least 5% of initial weight)
 and good compliance will be achieved given our previous experience.

 In aggregate, this study will investigate the effects of weight loss on (1) Rho kinase
 activity obtained from peripheral leukocyte (2). Aortic stiffness, central aortic pressure
 and hemodynamic by a noninvasive technique (3) Brain function specifically reflecting by
 circulating BDNF levels (4). Aortic elastic properties and left ventricular function by using
 MRI examinations, in non-diabetic individuals of metabolic syndrome. Findings from this
 integrated proposal will provide valuable information as mild to moderate weight loss (5% of
 initial body weight) in cellular, cardiac and central nervous system in additional to
 well-known effects on lipids, inflammatory cytokines and insulin resistance in non-diabetic
 subjects with metabolic syndrome.

 Follow up- Subjects received physical check up, fasting blood tests and OGTT 6 and 12 months
 after the end of study.
Inclusion Criteria:

 -  Age between 20 and 65 years

 -  Metabolic syndrome by IDF 2005 criteria

 Exclusion Criteria:

 -  known diabetes

 -  obesity due to endocrinologic disorders

 -  Psychological disorder or using psychological medications

 -  Abnormal liver function (three-fold upper normal limit)

 -  Abnormal renal function (1.5-fold upper normal limit)

 -  Investigator judgement for abnormal clinical data

 -  Life-threatening disease

 -  Acute infective status

 -  Alcohol or drug abuse

 -  pregnant potency without prevention

 -  receiving other clinical trial in recently three months