Increased plasma levels of glucose-dependent insulinotropic polypeptide are associated with decreased postprandial energy expenditure after modern Japanese meals

Obesity increases the risk of several health conditions, including hypertension, hyperlipidemia, and type 2 diabetes [1], and significantly increases healthcare costs. The World Health Organization (WHO) reported that more than one billion adults were overweight worldwide in 2009, with more than 300 million of them being clinically obese. According to WHO criteria, Japan had the lowest rate of obesity (approximately 3.9 %) among the OECD member countries in 2009 [2]. The onset and progression of obesity are closely related to lifestyle habits involving dietary patterns, physical activity, rest, tobacco use, and alcohol consumption.

Traditional Japanese dietary patterns are characterized by the high consumption of soybean products, fish, root crops, seaweeds, mushrooms, vegetables, fruits, and green tea [3]. Many epidemiologic studies have shown that the consumption of these food items or the adherence to a traditional Japanese dietary pattern in itself is inversely associated with lifestyle-related illnesses, such as cardiovascular disease, cancer, high blood pressure, high serum lipid levels, and diabetes [4‐7]. In addition, the traditional Japanese diet has drawn considerable attention since the 1960s because of its association with an extremely low rate of coronary heart disease [8].

However, the National Health and Nutrition Survey has revealed that dietary patterns in Japan are becoming increasingly westernized. The consumption of rice (a conventional staple food for Japanese), soy, and fish has been decreasing since the 1960s, such that meat and products containing wheat flour are now preferred by the Japanese population. Although the average total energy intake has not changed significantly, the consumption of dietary fat, especially animal fat, by the Japanese population has increased [3, 9]. Along with the observed changes in dietary nutrient composition, the number of overweight and obese Japanese is increasing, especially among men in their 30s to 60s. The 2008 report of the National Health and Nutrition Survey stated that 28.6 % of men and 20.6 % of women in Japan were considered to be obese or overweight [10]. Whereas an adverse dietary nutrient composition such as high fat content is known to increase the risk of obesity, how changes in nutrient composition affect energy balance in humans has yet to be elucidated.

Several mechanisms may explain the effect of nutrient composition on energy balance. One potential mechanism may involve the release of gastrointestinal hormones by specialized enteroendocrine cells after the ingestion of nutrients. Recent studies have shown that gastrointestinal hormones play an important role in regulating energy balance. For example, peptide YY (PYY) [11, 12], ghrelin [13‐16], glucose-dependent insulinotropic polypeptide (GIP) [17‐27], and glucagon-like peptide 1 (GLP-1) [17, 21, 25‐27] are known to regulate energy metabolism and appetite. Accordingly, these hormones have been the focus of increased interest due to their therapeutic potential for the treatment of obesity. In addition, several studies have proposed that dietary nutrient composition may influence the postprandial energy balance by regulating gastrointestinal hormones.

Therefore, the principal aim of the current study was to clarify how the nutritional changes associated with the modernization of the Japanese diet affect postprandial energy metabolism and gastrointestinal hormone responses. To this end, we compared postprandial energy expenditure and the postprandial blood levels of various metabolism-regulating hormones in healthy Japanese men after their consumption of traditional or modern Japanese meals.

This study yielded two key findings. First, the study demonstrated that the nutritional composition of our modern Japanese test diet increased postprandial GIP, TG, and active ghrelin responses compared with those of the traditional diet in healthy Japanese male adults. Second, we showed that the modern Japanese meals tended to induce less postprandial energy expenditure than did the traditional meals, especially after lunch, and were associated with increased postprandial GIP release.

Postprandial GIP release is stimulated by macronutrients, especially dietary fat [27, 30‐32]. The greater increase in postprandial GIP after the modern Japanese test diet seems to be due to its higher fat content compared with that of the traditional diet. In addition, the dietary fatty acid composition may have contributed to the increased GIP response after the modern meals. In the current study, the fatty acid composition (saturated/monounsaturated/polyunsaturated) was 5.9:6.7:9.1 g (27 %:31 %:42 %) for the traditional and 19.9:19.7:10.4 g (40 %:39 %:21 %) for the modern Japanese test diets. Monounsaturated fatty acids induce a stronger postprandial GIP response than do saturated fatty acids [30]. In addition, fish oil, which is rich in polyunsaturated fatty acids, suppresses the postprandial GIP response more effectively than do cocoa butter and olive oil [31]. Accordingly, the decreased polyunsaturated fatty acid content or the increased proportion of monounsaturated fatty acids (or both) may have contributed to the increase in the postprandial GIP response due to the modern Japanese test diet.

Like dietary fats, dietary protein increases postprandial GIP blood levels. Whey protein has been shown to stimulate postprandial GIP release into the blood [33]. Although the protein contents of the test diets were similar, the source of the protein differed between them: the traditional Japanese diet contained soy and fish, whereas the modern Japanese diet contained whey and meat as the main protein sources. The differences in the sources of dietary protein, which differed in amino acid composition, may have affected the postprandial GIP response. Additional studies are needed to clarify whether and how dietary protein differentially affects the postprandial GIP response in humans.

Regarding our second key finding, the results from our indirect calorimetry are consistent with the findings of Nagai et al. [34] and Maffeis et al. [35, 36], which showed that low-fat meals (energy %, 21, 20, and 27, respectively) induced greater thermogenesis postprandially than did extremely high-fat meals (energy %, 70, 48, and 52, respectively). Furthermore, our results parallel those from previous studies [34‐36], even though the difference in the total fat content between the two test diets (energy %, 14.8 and 27.5) was relatively low in our study.

The postprandial energy expenditure due to dietary protein is 20–35 % of the energy consumption [37]. Several studies have suggested that high-protein diets lead to greater energy expenditure than do low-protein diets [38]. In the present study, the modern Japanese diet (13.1 % protein) tended to induce less energy expenditure than did the traditional diet (14.4 % protein), especially after lunch, even though the protein content of the diets was similar. The different sources of dietary protein (soy compared with milk) might be responsible for the difference between the postprandial energy expenditures of the test diets. Additional studies are needed to clarify whether and how dietary protein differentially affects postprandial thermogenesis in humans.

Accumulated evidence suggests that GIP, through its specific receptor, plays an important role in the onset of obesity by promoting energy storage in adipose tissues [18‐26]. Several genome-wide association studies have identified single-nucleotide polymorphisms in the GIP receptor (GIPR) gene that are strongly associated with body mass index in humans [39‐42]. Moreover, another recent study showed that the GIP/GIPR gene polymorphisms were strongly associated with visceral fat accumulation in the Japanese population [43]. In addition, increasing the blood concentration of GIP through its intravascular infusion decreased REE in healthy humans [21]. We previously showed that postprandial REE is negatively correlated with the postprandial GIP response and that a test diet that stimulated decreased postprandial GIP release was more thermogenic than was the control diet in healthy humans [44].

Like those involving human subjects, animal studies support the claim that decreased GIP signaling increases energy expenditure and suppresses body fat accumulation. Our previous study demonstrated that increasing blood GIP levels through chronic administration of GIP reduced fat utilization in high-fat fed mice [45]. The genetic ablation of either the GIPR [22] or of GIP-secreting enteroendocrine cells [20] prevented the onset of obesity and increased fat oxidation under high-fat diets through an unknown mechanism. The GIP receptor is expressed in pancreas, stomach, small intestine, heart, adrenal cortex, brain, lung, bone, vascular endothelium, and adipose tissue [46]. Although skeletal muscle and liver are the predominant sites of body fat oxidation, they do not express the GIP receptor. As a possible mechanism for linking GIP and energy catabolism, Naitoh et al. [47] showed that chronic inhibition of GIP signaling increased plasma adiponectin levels, resulting in increased fat oxidation in the skeletal muscle tissues of mice fed a high-fat diet. Decreased GIP secretion may increase energy expenditure through the stimulation of adiponectin signaling. However, whether this mechanism holds true during the postprandial state of humans is unclear, because the blood adiponectin level did not change after meal ingestion by human subjects [48]. Additional research is needed to clarify the role of adiponectin in linking postprandial GIP and energy expenditure in humans.

The GIP receptor is expressed in pituitary, adrenal cortex [46], and brown adipose tissue [49], all of which play important roles in energy homeostasis, including diet-induced thermogenesis. Therefore, as another possible mechanism linking postprandial GIP and energy expenditure, the increased GIP signaling after the modern Japanese diet may somehow modulate these tissues and thus downregulate energy expenditure. However, the physiologic function of GIP in pituitary, adrenal cortex, and brown adipose tissue in relation to postprandial energy expenditure is unclear and warrants investigation.

Blood concentrations of active ghrelin were positively correlated with the postprandial REE after breakfast and lunch, suggesting that, like GIP, postprandial ghrelin is a robust indicator of postprandial thermogenesis and the magnitude of the increase in active ghrelin seems to dictate the increase in postprandial energy expenditure. However, the postprandial increase in ghrelin was greater after the modern Japanese meal than the traditional meal—a finding that is incompatible with the result that the postprandial energy expenditure was lower after the modern Japanese diet than the traditional diet. Accordingly, the increase in the active ghrelin response does not seem to be predominantly responsible for the increased postprandial thermogenesis after the modern Japanese meals. Although increasing levels of active ghrelin during fasting has been shown to stimulate the appetite [13‐16], the effect of ghrelin on energy expenditure has not been reported. Ghrelin increases hunger, food intake, and fat deposition by binding to its specific receptor in the ventromedial hypothalamus [50, 51]. In addition, electrical stimulation of the ventromedial hypothalamus of rats increased energy expenditure [52] and thermogenesis in brown adipose tissue [53]. Accordingly, ghrelin may increase energy expenditure through a hypothalamic mechanism. In one study [54], higher fasting blood ghrelin levels were associated with lower DIT, suggesting that ghrelin plays a significant role in regulating postprandial energy expenditure. In contrast, the role of the postprandial blood ghrelin response in regulating DIT remains to be clarified. In this regard, a high-protein diet was reported to increase postprandial thermogenesis but to blunt the postprandial blood ghrelin response [55]. However, blood ghrelin levels did not differ between the high-protein and the protein-sufficient diets in another experiment [56]. The relationship between the postprandial blood ghrelin response and DIT is therefore unresolved still.

The postprandial blood GIP response was negatively correlated with postprandial REE after the modern Japanese lunch but not after the traditional lunch (Fig. 4d). One possible explanation for this inverse correlation only after the modern Japanese lunch may be due to the concurrent increases in blood GIP and TG concentrations during and after the meal. Studies have shown that GIP increases the synthesis and secretion of lipoprotein lipase (LPL) in adipocytes [23, 57] and promotes the activity of LPL in fat tissue [58]. When the drop in LPL activity due to decreased GIP signaling in adipose tissue coincides with increased blood TG levels, the amount of fat released into the circulation may increase. In fact, ingestion of the modern Japanese diet (27.5 % fat content) increased the blood TG response more than twice that induced by the traditional diet (14.8 % fat content) (Fig. 1c), and the postprandial GIP response after the modern diet was almost double that after the traditional diet (Fig. 1d), supporting the hypothesis that concurrent increases in blood GIP and TG increase the amount of fat distributed to the circulation. When the postprandial GIP response is decreased in the context of increased blood TG, more fat may be distributed to energy-utilizing tissues such as skeletal muscle and liver, both of which lack the GIP receptor, to a greater extent than to energy-storing adipose tissues, thus increasing fat oxidation. However, the precise link between postprandial GIP signaling and whole-body energy utilization remains unclear and merits additional research.

Correlation analysis revealed that the iAUCs for the postprandial blood responses of CCK and active GLP-1 were not associated with postprandial REE in the current study, in contrast with the well-known correlation between GLP-1 and postprandial energy expenditure in other studies [59, 60]. The reason for these differing results is unclear but may reflect differences between the study protocols, including the dose of GLP-1. In addition, the postprandial increase in the blood level of active GLP-1 that we obtained in the current study was smaller than those in other studies [59, 60]. Additional work is needed to clarify the role of GLP-1 in postprandial energy expenditure.

According to the National Health and Nutrition Survey in Japan, the composition of the Japanese diet has changed markedly since 1960. However, the effect of dietary composition on energy homeostasis has been little investigated. The model composition of the average Japanese diet in 1975 was less obesity-inducing than was that in 2005 [61]. In the current study, the postprandial thermogenesis after the modern Japanese lunch was 1420 kJ less than that of the traditional Japanese lunch on average, which corresponds to 1.1 kg body fat per month. These results suggest that the nutritional change that accompanies the modernization of the Japanese dietary composition may increase body fat accumulation. The results of our current study also suggest that the postprandial GIP and active ghrelin responses are reliable predictors of postprandial REE and might be used as markers for designing obesity-preventive meals. In addition, our previous studies have consistently demonstrated that decreasing the diet-induced GIP response leads to increased energy expenditure and prevents high-fat diet-induced obesity in mice [44, 62].

A potential weakness of the present study is that our study population was small. Using a larger study population would be valuable for clarifying whether modern Japanese meals are less thermogenic than are traditional Japanese meals. Another limitation is that we did not address the mechanisms underlying the negative correlation between the postprandial GIP response and postprandial REE. Although GIP is well known as an incretin hormone that potentiates glucose-induced secretion of insulin from pancreatic β cells, blood insulin levels did not differ postprandially between the test diets. Accordingly, the extrapancreatic action of GIP—rather than its insulinotropic action—seems to facilitate the downregulation of postprandial energy expenditure. Additional studies are needed to clarify how blood GIP lowers postprandial thermogenesis. Another limitation of the present study is that the mechanisms underlying the positive correlation between the postprandial active ghrelin response and postprandial REE remain elusive. The contribution of the increase in ghrelin content to the decreased postprandial energy expenditure after the modern diet warrants further investigation.

In conclusion, the current study demonstrates that the modern Japanese test diet induced greater postprandial blood GIP and ghrelin levels than did traditional Japanese meals, and these hormonal responses were associated with postprandial thermogenesis in healthy Japanese men. We believe that not only the increased calorie intake but also the changes in the macronutrient composition that accompany the modernization of Japanese dietary patterns cause body weight and fat gain by altering the release of metabolism-regulating hormones to become more anabolic. The results of our study also indicate that the meal-induced release in the intestinal anabolic hormone GIP and the gastric hunger hormone ghrelin may be markers of postprandial thermogenesis and therefore may facilitate the design of obesity-preventative meals. The pairing of an increased postprandial ghrelin response with reduced the postprandial energy expenditure after the modern Japanese diet was inconsistent with the positive correlation between postprandial ghrelin response and energy expenditure; however, these data are inconclusive and merit further study. Our on-going studies seek to clarify whether and how the daily consumption of “low GIP meals” decreases body weight and fat mass in obese and overweight subjects. Additional detailed studies on the relationship among diet-induced GIP and ghrelin responses and postprandial energy homeostasis are warranted.