Factors which predict variance in weight change

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications, trials & patents

Abstract

In order to investigate how energy expenditure changes with over and underfeeding the following studies are underway. In one study, after careful calibration of weight maintenance EE, individuals undergo a series of measurements of 24 hour EE in a respiratory chamber in which they are fasting or overfed (by 200% of weight maintenance needs) a series of diets that vary in macronutrient content. This is to further investigate whether low or high protein diets may improve the detection of recruitment of adaptive thermogenesis. In addition, behavioral, metabolic and hormonal tests are performed to examine associated characteristics and to investigate the mechanism of the changes in EE. These individuals are followed up long term (up to 7 years) to investigate whether these energy expenditure phenotypes predict weight change. We have demonstrated that the change in energy expenditure with fasting and with overfeeding is reproducible. We have had 96 participants complete the core portion of this study. Consumption of high carbohydrate and high protein overfeeding diets increased EE the most, while low protein overfeeding increased EE the least. Individuals with a greater increase in EE with overfeeding have less decline in EE with fasting indicating the presence of thrifty versus spendthrift energy expenditure phenotypes. After 6 months, we found that several EE phenotypes predicted weight gain: 1. Individuals with greater decrease in EE with fasting 2. Individuals with less increase in EE with low protein overfeeding 3. Individuals with greater increase in EE with high carbohydrate overfeeding. Increased EE after high carbohydrate overfeeding was also associated with greater hunger. Our data also demonstrates that macronutrient composition largely determines fuel preference (carbohydrate versus lipid oxidation rates) and that extrinsic dietary factors account for approximately 20% of the variance in these measurements. However, there is a strong intra-individual component to fuel preference with carbohydrate oxidation rates. In addition, greater metabolic flexibility (those who decreased their 24hRQ and lipid oxidation rates more) determined during 24 hours of high fat overfeeding was associated with less weight gain, gained less (or even lost) weight. In further examining the thrifty versus spendthrift phenotypes, we have found that the greater drop in 24hEE with fasting, is due to a higher energy balance 24hEE rather than a lower fasting 24hEE. Thus, thrifty subjects have a higher energy balance 24hEE compared to spendthrift. Spendthrift subjects increase their EE during sleep. Furthermore, during protein imbalance overfeeding, thrifty individuals have blunted increase in 24hEE. These analyses fundamentally recharacterizes the prevailing model of the thrifty vs. spendthrift phenotype as we have defined it. We have also extended the thrifty versus spendthrift phenotype to EE changes with cold exposure. Individuals who have greater increase in 24hEE during mild cold exposure (19C) have less decrease in 24hEE with fasting. We have been investigating the mechanisms underlying these energy expenditure changes to fasting and overfeeding. One measure of the ability to dissipate heat is changes in core body temperature. Core body temperature correlated with changes in EE in response to fasting, such that individuals with lower core body temperature have a greater decrease in EE with fasting. Core body temperature increases with overfeeding, and in the setting of a high fat diet, this increase is associated with an increase in EE. We have also examined the role of the sympathetic nervous system. Urinary epinephrine excretion increases with fasting. We have found that there is an association between the increase in urinary epinephrine excretion and change in EE during fasting such that individuals who decrease fasting less have greater increase in urinary epinephrine excretion. Fibroblast growth factor 21 (FGF-21) is secreted by the liver and increases EE in rodent models. In humans FGF-21 increases with low protein diets. We found that FGF-21 increased substantially (by 300%) following two different low protein overfeeding diets and that increased change in FGF 21 concentrations correlated with greater %EE increased with low protein overfeeding. Moreover, the greater increase in FGF-21 concentrations were associated with less weight gain at 6 months. Most significantly, this increase in FGF-21 mediated the association between greater increase in %EE with low protein overfeeding and weight change at 6 months indicating that FGF-21 is a good target for weight loss treatment. FGF-21 also decreases with 24h of fasting and cold exposure. We have consistently found that less decrease in FGF-21 is associated with less decline in EE during sleep (a surrogate of resting EE). This was also true during cold exposure, less decline in FGF-21 was associated with relatively greater increase in Sleeping EE during mild cold exposure. We also found a possible role for ghrelin the thrifty phenotype. In examining the growth hormone (GH) axis role in EE changes, we found that fasting induces GH hypersecretion independent of changes in ghrelin and without changes in its downstream mediator insulin-like growth factor-1. However, we found that individuals who increase ghrelin more with fasting had greater decrease in 24hEE. We have also found that urinary dopamine concentrations also increase during fasting and low protein overfeeding and are associated with changes in pancreatic polypeptide indicating a shift in sympathetic/parasympathetic tone with protein deprivation. We have found that while thyroid hormones do change with fasting and with low protein and high protein overfeeding diets, these changes are not related to changes in energy expenditure. Thus, diet induced thermogenesis does not appear to be mediated by the thyroid hormone axis. We are continuing long term follow-up of those with these energy expenditure measurements and investigating the role of gastrointestinal, inflammatory and adipocyte hormones as possible mediators of these EE changes and or weight change. As increased adiposity may insulate against trans-abdominal heat loss which may increase TEF, we investigated the effect of central insulation on the EE and TEF changes associated with overfeeding. However, despite earlier evidence of an important role of abdominal heat dissipation in determining DIT and TEF, we did not find any changes in EE during overfeeding with additional abdominal insulation. Because of the recent discovery of the presence of brown fat in humans and its possible role in thermogenesis, we performed positron emission scans with labeled glucose. As brown fat is activated by cold temperatures, we have established that we can visualize brown fat after 2 hours of exposure to 16 degrees Celsius. We then currently investigated whether individuals with visualized brown fat after cold exposure, have visualized brown fat after overfeeding. Following demonstration of visible brown fat after cold exposure individuals were overfed by 200% of their energy needs using a high fat normal protein diet while in our metabolic chamber. The next morning, they underwent a PET-CT scan; this was performed in some individuals prior to breakfast (approximately 12 hours after their last overfeeding meals) and in some individuals following a similar overfeeding breakfast (approximately 4 hours after their last meal). We found no evidence of activation of brown fat with overfeeding following a high fat overfeeding, indicating that brown fat does not mediate the increased energy expenditure associated with overfeeding. Based on evidence of brown fat activation with high carbohydrate overfeeding, we have used the same overfeeding paradigm with our high carbohydrate over