Findings from our case control study showed that there is no significant difference between the median appetite and hormones of leptin, ghrelin and insulin between the two groups with normal metabolism and impaired metabolism. But there is a positive relationship between insulin levels with RMR and there is a negative relationship between ghrelin levels with RMR, there is also a positive relationship between appetite and the rate of hunger with RMR, which remained significant after adjusting for confounder (body fat percentage).
Resting metabolic rate, which is one of the main determinants of energy expenditure (60-70%), can be related to the amount of energy intake per day and eating behaviors. Studies have shown that RMR is an important determinant of meal size and energy intake per day (12). RMR is also said to be a predictor of fasting hunger and affects the overall hunger profile. So RMR as an energy expenditure component reflects the physiological need for food intake. This hypothesis is in line with Edholm's theory that the difference in food intake is due to the difference in energy expenditure (47).
In our study, the results of appetite in the case and control groups indicate a significant direct relationship with RMR. Also, in examining the indicators of the appetite questionnaire(46) with resting metabolic rate, we found that there is a positive relationship between hunger and RMR, which remained significant after adjusting for the confounding variable, which was in line with the results of the study by Caudwell et al.(10). Another point is that there is a paradox that says why in obese and overweight people who have high fat mass and a high amount of energy stored in their body, the tendency to eat and hunger is high, in fact one of the reasons is that, in these people, due to high fat mass, high lean mass (FFM) is also high and FFM is one of the important determinants of RMR, and the higher the RMR level, the higher the rate of hunger and appetite is (10).
In the present study, the hypothesis that the serum level of leptin hormone is associated with resting metabolic rate in the two groups with normal and impaired metabolism was not accepted, which could be due to the low number of samples in the groups. In general, several studies have been conducted to investigate the relationship between leptin and obesity. This indicates that the majority of obese people have higher blood leptin levels than normal people (90%) and the amount of leptin in the blood increases in proportion to the amount of body fat, especially subcutaneous fat, so that there is a direct relationship between the serum level of leptin and its BMI (48). There is evidence to suggest that leptin is involved in regulating energy metabolism. Energy metabolism and body temperature increased in ob/ob mice after leptin injection (49-51).
In our study, the results of leptin in the case and control groups showed no difference between the two groups and no significant association was observed between this hormone and RMR, which was in line with the results of the study by Neuhauser et al.(52). Human studies examining the relationship between leptin hormone and RMR have published conflicting results, some of which have reported no association between RMR and leptin levels in adults (31-33). Some studies also reported a positive association (34, 35), and some a negative association (36). One of the reasons for these contradictory results may be differences in procedure. When we want to study the relationship between leptin and RMR, body composition, FM, FFM is very important and these variables must be considered. While many of these studies reported a positive association, did not pay attention to these variables. In fact, because one of the most important determinants of serum leptin is body fat (34) and in our study, all the samples were obese and overweight, and these two groups were matched based on BMI and age, so it may be the reason for not seeing a difference in leptin levels between the two groups.
We found that there is a negative relationship between serum ghrelin levels and resting metabolic rate in two groups with normal and impaired metabolism. There is evidence to suggest that ghrelin is involved in energy metabolism, especially in regulating food intake (53-60).
In our study, the results indicate a significant inverse relationship of ghrelin hormone with RMR, which is in line with the results of Marzullo et al.(61). The Marzullo study, which investigate 20 obese and 20 lean samples for metabolism and ghrelin levels, found that serum ghrelin levels were 30 percent lower in obese people than in normal people, and with increasing adipose tissue ,there is decrease in leptin and insulin, ghrelin levels. In addition, ghrelin levels decrease less after eating in obese people (62-64). Although an increase in ghrelin levels causes weight gain by increasing food intake and decreasing the energy metabolism and fat catabolism (30, 55, 65).The effect is primarily due to increased calorie intake and the shift of cells from fatty acid oxidation to oxidation of glucose (30, 55).The relationship between ghrelin and energy metabolism levels in obese and overweight people needs further investigation(66). Some studies have shown different results from our research. A study by Ravussin et al. On non-obese identical twins did not show a significant relationship between ghrelin levels and positive and negative energy balance(30). The reason is that ghrelin has two different and contradictory effects on the human body through the somatotropic effect of growth hormone, which leads to a decrease in fat mass and an increase in lean mass, and through the adipogenic effect of ghrelin, leading to an increase in food intake and a decrease in fat oxidation. In fact, people with higher ghrelin levels for the same size and body composition will gain more weight due to overeating and less weight loss due to negative energy balance(30).However, ghrelin is expected to intervene endogenously to improve impaired metabolism (29). In an interventional study conducted in 2018 by Allas et al., They found that injection of non-acylated ghrelin analog (AZP-531) reduced waist circumference and fat mass in humans without changing weight (67).Another human study by Allas et al. in 2016 found that injecting non-acylated ghrelin analogues in obese and overweight adults, decreased weight 2.6 kg and also improved glucose levels without increasing insulin (68). In our study, we found that with the increasing level of ghrelin, carbohydrates per day burned as a substrate for energy (which comes from the result of RMR test) reduces (p-value=0.01). This is in line with a study by Wortley et al.2004, they observed that endogenous ghrelin plays an important role in determining the energy substrate (53) and also conflicting with previous studies which demonstrate that increasing level of ghrelin causes shift of the cells from fatty acid oxidation to oxidation of glucose and ultimately leads to the accumulation of fat in the body (30, 55).Therefore, the possibility that ghrelin intervenes to improve the level of impaired metabolism should be considered.
The present study demonstrates that the serum level of insulin hormone is associated with RMR in two groups with normal and impaired metabolism. In fact, the results showed that in general, the higher the level of insulin hormone, the higher the resting metabolic rate, which is in line with the results of Drabsch et al. (69).Hemostatic regulation of glucose is through the action of the hormone insulin in adipose tissue, muscle and liver tissue. Insulin is an anabolic hormone and is made and stored in the granule cells of the islets of Langerhans. And is secreted in response to an increase in blood glucose concentration (70).The main function of this hormone is to transport glucose into muscle cells and adipose tissue, which causes glycogen synthesis and lipogenesis, and inhibits gluconeogenesis in the liver. In general, one of the main functions of insulin is to focus on tissues that regulate energy metabolism (71).The results of our study demonstrate that insulin hormone in the case and control groups indicate a significant positive relationship with RMR, which is consistent with the results of the study of Ravussin et al. Through the Euglycemic Insulin clamp technique, the thermic effect of insulin and glucose injection can be studied in detail. In this technique, RMR is measured by indirect calorimetry during insulin and glucose injections. The results of several studies have shown that between 50-70% increases in the level of resting metabolism is due to glucose injection and rising insulin levels and conversion of glucose to glycogen (72-74).