Growth Hormone as a Determinant of Weight Regulation
Condition: Obesity
Study type: Interventional

Summary: 
      With the alarming increase in the prevalence of obesity, identifying factors that predispose
      individuals to weight-gain is of critical importance. Even when caloric intake and physical
      activity levels are well controlled, susceptibility for weight-gain is heterogeneous. Basal
      metabolic rate (BMR) represents the largest portion of daily energy expenditure in normal
      adults, and as such, variability in BMR among individuals can be a major factor in
      determining the susceptibility for gaining weight. However, factors responsible for this
      variability in BMR and resistance to weight-gain remain unclear. Our preliminary data
      indicate that high-normal growth hormone (GH) concentration is associated with resistance to
      weight-gain in rats when overfed and greater weight-loss in humans when underfed. In
      addition, the investigators have found that the pulsatility of GH secretion has profound
      effects on several metabolic processes. Therefore, together these findings suggest that
      endogenous GH secretion is associated with body weight regulation, and the pulsatility (peak
      amplitude) of GH secretion, rather than the absolute GH concentration, per se, may be
      responsible for this effect. Because GH influences many of the key metabolic processes that
      contribute to BMR (e.g.; protein synthesis, proteolysis, substrate cycling), the
      investigators anticipate that the resistance to weight-gain in persons with elevated GH
      concentrations will be associated with an increase in BMR due to acceleration of some or all
      of these processes. Our overall hypothesis is that increased GH secretion can protect against
      weight-gain due to an augmentation of major metabolic processes that contribute to BMR.
      Identifying factors responsible for predisposing individuals to weight-gain will lead to
      establishing improved methods for reducing the prevalence of obesity.
    

Detailed description: 
      The susceptibility to gain weight is highly variable even when caloric intake and physical
      activity are well controlled. Because basal metabolic rate (BMR) represents ~70% of total
      daily energy expenditure (TDEE), even a small difference in BMR can affect daily energy
      balance, thereby increasing the susceptibility for gaining weight. Our preliminary data
      indicate that high-normal growth hormone (GH) secretion is associated with resistance to
      weight-gain in rats when overfed and greater weight-loss in humans when underfed. Given that
      GH influences many of the key metabolic processes that contribute to BMR, the investigators
      hypothesize that persons with high-normal GH will be resistant to weight-gain because of a
      high BMR, resulting from accelerated rates of these processes. The investigators will measure
      basal 24h GH secretion and BMR in 106 non-obese men and women. The investigators will also
      measure protein synthesis, proteolysis, triglyceride/fatty acid cycling (all measured using
      stable isotope tracer methods) to determine the relationships among these processes, BMR, and
      GH [Specific Aim 1]. Subjects identified as having "low-normal" (<1.5 ug/L) and "high-normal"
      (>3 ug/L) 24h GH will then be admitted to the hospital for a 2 wk overfeeding protocol (~2000
      kcal/d >TDEE - with restricted physical activity), immediately followed by a 4 wk caloric
      restriction protocol (~750 kcal/d <TDEE) to compare changes in weight, body composition and
      intra-abdominal adiposity between these groups that differ markedly in their GH secretion (GH
      measured before the diet) [Specific Aim 2]. A subset of subjects with low-normal GH will
      receive intravenous GH throughout the 2 wk overfeeding period at either: 1. a constant rate
      or 2. as a pulsatile infusion (to mimic endogenous secretion). BMR will be assessed daily and
      protein synthesis, proteolysis, and triglyceride/fatty acid cycling will be measured at the
      end of the 2 wks [Specific Aim 3]. The investigators anticipate that a higher GH pulsatility
      (peak amplitude), rather than elevated GH concentration, per se, will increase protein
      synthesis, proteolysis, and triglyceride/fatty acid cycling with a resultant increase in BMR
      and resistance to weight-gain. Identifying factors responsible for predisposing individuals
      to weight-gain will help combat the alarming rise in the prevalence of obesity.
    

Intervention name(s): overfeeding; growth hormone treatment
Intervention type(s): Other; Drug
Intervention description(s): overfeeding 2000kcals/day above energy requirements for 14d; growth hormone administrated for 2 weeks (dose = 1.0 mg/m2/d)
Intervention MeSH terms: Hormones
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: growth hormone; overfeeding; energy expenditure; protein metabolism; lipid metabolism