In this dietary intervention study, adherence to either HP or LP diet resulted in reduced concentrations of various inflammatory biomarkers in people with morbid obesity. Results were especially pronounced for CRP and chemerin, two biomarkers reflecting inflammation and cardiovascular risk. Following LP diet was also associated with decrease in leptin and IL-6 concentrations and an increase in adiponectin concentrations. Effects were less prominent for the remaining biomarkers. To our knowledge, this is the first intervention study that explored the effects of varying amounts of dietary protein on changes in various immune-inflammatory biomarkers in people with morbid obesity.
Our results suggested that LP diet was associated with a wider range of beneficial effects including reducing concentrations of CRP, IL-6, chemerin, and leptin and increasing total adiponectin concentration, whereas the effect of the HP diet was most pronounced for reduced CRP and chemerin concentrations. LP diet can be also characterized by reduced exposure to methionine and a number of animal studies have shown that methionine restriction modulates metabolism and improves health span (24, 25). Low-methionine diets have shown to decrease inflammation (24, 26, 27), reduce adiposity (28, 29), decrease oxidative stress (30), and increase insulin sensitivity (28, 31, 32). Compared to calorie restriction, responses to methionine restriction were found to be more robust over the long-run (27). Dietary methionine restriction has been especially associated with metabolic changes in adipose tissue and liver resulting in enhanced insulin sensitivity and energy expenditure (33). In animal studies, methionine restriction was shown to reduce concentrations of insulin, insulin-like growth factor‐1, glucose, and leptin and increased adiponectin (33). However, evidence from human research has been sparse. In a large cross-sectional study of US adults, methionine-rich diets were associated with a higher prevalence of cardiometabolic disease risk factors, i.e. higher levels of cholesterol, glucose, glycated hemoglobin, uric acid and insulin (33). The concentrations of CRP also showed to be higher with higher intake of methionine-rich diet, albeit the trend did not reach statistical significance. A randomized trial that evaluated the effect of a 16-week methionine restricted intervention (> 80% relative to controls), showed that people with obesity and metabolic syndrome had increased adiponectin concentrations (34). As our participants in the LP group received both calorie restricted diet with reduced methionine, a next step would be to reproduce the beneficial effects of the methionine restricted diet in people with morbid obesity without imposition of severe calorie restriction.
The beneficial effects of HP were restricted to reducing concentrations of CRP and chemerin. These results are in line with our previous work, where we evaluated the effect of HP diet in a 6-week intervention study among diabetes patients with obesity (21). HP has a stronger effect on satiety compared to diets of LP content and with equivalent quantities of E from carbohydrate or fat (35). Although there is no formal definition of ‘high-protein’ as percentage of E in a diet, above 25% E can be seen as high based on a review on satiety and US dietary recommended intakes (36). The effects seen in HP diets may be explained by the high-protein content per se, however, they may also be confounded by other components in the diet. The HP diet in this study and in our previous study contained dairy components. In particular, fermented dairy products (i.e. yoghurt) have been associated to lower levels of inflammation in observational and intervention studies (37, 38). These anti-inflammatory effects could be possibly accounted for by beneficial properties of bacteria species (39) and bioactive peptides that interact with gut microbes and immune cells (40). Further work would be warranted to explore the influence of dietary interventions on gut microbiota composition and immune status in people with morbid obesity.
Up to date, there is still no consensus as to which biomarkers may best represent low-grade inflammation (41). Most dietary intervention studies have been limited in the range of evaluated inflammatory biomarkers (11). CRP is the most established biomarker of inflammation, often used as proxy, sometimes together with IL-6 that stimulates production of CRP. However, CRP alone may not sufficiently capture the effect of diet on the complete inflammatory phenotype associated with obesity. We therefore assessed additional circulating molecules that have been suggested as biomarkers of increased risk and contributing to the pathophysiology of comorbidities of obesity. We were especially interested to evaluate established adipokines such as adiponectin and leptin, as well as novel proinflammatory adipokines, i.e. omentin, chemerin and MCP-1 shown to induce insulin resistance, endothelial dysfunction, and systemic inflammation (42). We were further interested in specific immune-related biomarkers, i.e. chemokines and cytokines that mediate both immune cell recruitment and complex intracellular signaling control mechanisms in obesity, inflammation and chronic disease development (43). Finally, we focused on fetuin-A as biomarker of fatty liver and inflammation, known to exert important roles in in the pathophysiology of insulin resistance and atherosclerosis (44).
This study also has several limitations. We used data from a clinical trial that was designed and powered to study the effects of LP and HP diets on changes in liver fat, whereas the outcome of our study was changes in inflammatory biomarkers. The sample size was relatively small which could have influenced the precision of the observed results. In addition, the duration of the intervention was short, so how long the effects of the intervention will last and whether similar effects will be seen on the long run is to be elucidated. Furthermore, the intervention consisted of a hypocaloric diet, so participants lost weight. The caloric restriction of these patients may have acted as an activator of protective metabolic pathways, in addition to protein intake or methionine restriction. In the analysis we adjusted for BMI change pre-post intervention, however, the molecular mechanisms underlying the effects of dietary protein or the metabolic effects of weight change may not have been captured sufficiently by the adjustment of BMI. We conducted this study to see whether a change in protein content or methionine restriction in terms of the hypocaloric diet could improve inflammation. If the participants maintained their usual caloric intake, the effects of protein or methionine per se would have been captured better. As there are a number of modifying factors that affect the concentration of an inflammatory marker at a given time (45), including age, diet and body fatness, among others, we controlled (diet) or corrected (age, sex, BMI) for these in our analyses.