Re-energize With Nutrition, Exercise and Weight Loss
Condition: Obesity
MeSH terms: Obesity
Study type: Interventional

Summary: 
      The purpose of this project is to establish a Center of Excellence in Research on Obesity
      that will focus on severe obesity. The prevalence of severe obesity (i.e., Class 2 and 3
      obesity; body mass index > 35 kg/m2 and 40 kg/m2) is increasing more rapidly than is
      overweight and Class 1 obesity. Treatment guidelines for severe obesity are uncertain.

      Three novel hypotheses regarding the pathogenesis of severe obesity will be tested: a) using
      non-invasive methods to measure energy expenditure; b) conducting an annotated lipomic search
      for bio-markers of impaired fat oxidation; and c) examining the role of obesity-induced
      inflammation as a cause for leptin resistance. Responses will also be measured following
      intervention with diet and activity.
    

Detailed description: 
      SPECIFIC AIMS The first specific aim is to examine mechanisms for the pathogenesis of severe
      obesity.

      Obesity is a heterogeneous and complex metabolic disorder. The pathogenesis of obesity
      remains obscure and it is unclear why some individuals are prone to severe obesity. It is
      also unclear why there are ethnic and racial differences for severe obesity. Many scientists
      postulate that metabolic vulnerabilities for obesity can be identified in the severely obese.
      The 1st specific aim examines the pathogenesis of severe obesity with three research
      protocols applied within the same cohort of research participants.

        1. energy expenditure. Some prior studies indicate lower rates of resting energy
           expenditure (REE) in African-Americans, posing a metabolic risk for weight gain and
           resistance to weight loss. Other recent work highlights an important role for
           non-exercise activity thermogenesis (NEAT) in the pathogenesis of obesity. There are
           limited data addressing energy expenditure in severe obesity. In 120 severely obese
           adults (50% Class II and 50% Class III; with 50% African American participation), energy
           expenditure will be studied at baseline and after 6 months of intervention. The
           doubly-labeled water method will be used to measure total daily energy expenditure
           (TEE). Indirect calorimetry will be used to measure resting metabolic rate (RMR).
           Physical activity will be measured using light-weight, wearable monitors. NEAT will be
           calculated using these measurements. Comparisons will be between the groups with Class
           II and III obesity with further analysis for effects of ethnicity. These findings will
           be compared to data obtained in lean control subjects. The effect of intervention will
           be examined. This cohort will have a 1 year intensive behavioral weight loss
           intervention. Half of the volunteers will be randomized to a combined diet and exercise
           intervention (DE) , and the others will be randomized to diet intervention only for the
           initial 6 months, adding the exercise component at 6 months (DE-DELAY).

        2. impaired capacity for fat oxidation. In these participants, a drop of blood will be
           obtained at baseline and 6 months, for a low-cost, high throughput, yet highly detailed
           tandem mass spectroscopy profile of plasma levels of acylcarnitines. Elevated levels
           will denote disorders of fatty acid oxidation and selective increase in specific
           acylcarnitine species will denote particular enzymatic loci of impairment. This aim
           derives from rapid recent progress in two parallel field of metabolic investigation. One
           of these is the field of "inborn errors of metabolism", a field generally applied to
           newborns and children. In this field there has been a rapid increase during the past
           decade in recognizing and delineating in-born errors of fatty acid oxidation. Profiling
           plasma levels of acylcarnitine species is a standard diagnostic approach. In obesity
           research, a strong body of data have been developed during the same interval that one of
           the key metabolic impairments is mitochondrial dysfunction and reduced capacity for
           fatty acid oxidation in skeletal muscle. Racial differences in muscle oxidative capacity
           have been reported, with lower values for oxidative capacity in AA women,
           characteristics postulated to be a metabolic risk factor for obesity. We propose
           inter-action of these two lines of investigation, exploring the utility of tandem mass
           spectroscopy screening for plasma acylcarnitines as a non-invasive probe of metabolic
           impairments in the severely obese.

        3. leptin resistance. The third protocol to be used in this group of severely obese
           concerns a novel concept for leptin resistance. A decade ago, the discovery of leptin
           was pivotal in renewing scientific interest in obesity. Leptin modulates appetite and
           energy expenditure, two processes fundamental to weight regulation. Yet, treatment of
           obesity with leptin has failed to meet expectations. This has been attributed to "leptin
           resistance". This protocol will examine the role of serum leptin interacting proteins
           (SLIPs) that bind leptin as a factor contributing to leptin resistance. This line of
           basic science research indicates that one of the SLIPs is C-reactive protein (CRP) which
           suggests that low-grade inflammation, a metabolic complication of obesity related to
           risk for cardiovascular disease (CVD) may also contribute to the pathogenesis of
           obesity. There are common themes in these three protocols that form Specific Aim 1. Each
           addresses an aspect of the regulation of energy expenditure and fat oxidation. Each has
           the potential to identify novel bio-markers. Each project employs state-of-the-art
           analytical procedures, yet uses only minimally invasive sample collections. Finally,
           each will be carried out in the full research cohort of Phase 1, at baseline and during
           intervention, comparing metabolic effects of DE versus DE-DELAY. Though physical
           activity may be more important for weight loss maintenance than induction of weight
           loss, it has been found to increase capacity for fat oxidation more than weight loss
           induced by diet. It is from this latter perspective that we are interested in
           comparisons of DE and DE-DELAY at 6 months using these metabolic parameters.

      The 2nd specific aim is to develop an effective intervention for the severely obese.

      Axiomatic in the contemporary approaches to treatment of obesity is that clinically
      significant benefits are obtained with modest weight loss. This principle underlies the
      consensus recommendations for a weight loss target of 5 to 10% for overweight and obese
      individuals. The 2nd specific aim is to implement a behavioral dietary and physical activity
      intervention and assess whether this achieves a target weight loss at 1 year of ≥ 7% in Class
      II and Class III obese research participants. 120 adults, as described above, will have a 1
      year intervention. Intervention to increase physical activity in the severely obese may be
      particularly challenging. Possibly this is easier after a period of weight loss. The staging
      of diet and physical activity (DE versus DEDELAY) will examine this.

      The 3rd specific aim is to assess the effect of intervention on adverse health risks.

      The medical rational for weight loss and physical activity is to improve health and
      ameliorate adverse effects of obesity. The 3rd specific aim is to assess the impact of
      intervention in the Phase 1 cohort. A panel of standardized clinical measurements, laboratory
      tests, and self-report instruments will be performed at baseline, 6 months and 1 year. We
      will examine: 1) traditional cardiovascular risk factors (e.g. hypertension, dyslipidemia,
      glucose and insulin, along with other endocrine measurements); 2) markers of inflammation,
      adipokines and cytokines; 3) body composition and regional distribution of adipose tissue; 4)
      functional status (a timed 400 meter corridor walk); 5) sub-clinical vascular disease (pulse
      wave velocity and carotid ultrasound); 7) health history and use of medications; and 8)
      demographic indices, social and neighborhood factors, quality of life, impact of obesity, and
      self-perception of body image and discrimination. One line of inquiry concerns the role of
      baseline characteristics in accounting for heterogeneity between individuals in adverse
      effects of severe obesity. The second line of inquiry is to assess the impact of intervention
      to change these parameters.
    

Intervention name(s): Diet and Exercise; Diet and Exercise-Delayed
Intervention type(s): Other; Other
Intervention description(s): The participants in this intervention will receive 12 months of weight loss through diet and exercise; Participants in this intervention will receive six months of weight loss through diet followed by six months of diet and exercise
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: Body Fat; Exercise; Metabolic syndrome; Obesity; Nutrition; Physical Activity; Weight Loss