Interrelationships Among Accumulations of Intra- and Periorgan Fats, Visceral Fat, and Subcutaneous Fat

Excessive accumulation of visceral fat is known to induce chronic inflammation, hypoxia, high levels of oxidative stress, and abnormal production of adipocytokines, leading to disturbances in glucose and lipid metabolism. Furthermore, in recent years, it has been reported that fat accumulations in intra- and periorgans, such as the pancreas, liver, skeletal muscle, and renal sinus, lead to glucose disturbances (1) and organ dysfunction through inflammation and fibrosis (2–5). Although these conditions have gained attention in connection with intra- and periorgan fats (also known as ectopic fat), the relationships between intra- and periorgan fats, visceral fat, and subcutaneous fat remain unclear. The purpose of this study was to comprehensively evaluate intra- and periorgan fat accumulations (in the pancreas, liver, renal parenchyma, renal sinus, skeletal muscle, and spleen), visceral fat, and subcutaneous fat and clarify the relationships among these fat accumulations.

We recruited patients aged >20 years at Osaka University Hospital, a large 1,086-bed community academic hospital, who underwent abdominal computed tomography (CT) scans for underlying diseases during their inpatient admission or within 3 months before admission between June 2021 and August 2022. We excluded patients with pancreatic diseases (e.g., pancreatic tumor, pancreatitis), liver diseases (hepatitis, liver cirrhosis), kidney diseases (kidney cancer, end-stage renal disease), adrenal diseases (Cushing syndrome, pheochromocytoma), and acute-stage infections. Approval for the study was granted by the institutional ethics review board of Osaka University Hospital (Suita, Japan), with the assigned approval number 21062. Participants were provided with information about the study and gave written consent to participate.

We used unenhanced CT attenuation to gauge the extent of intra- and periorgan fats, which have been shown to have a robust correlation with histologically determined organ fat content (6). As previously reported (7), we computed the CT attenuation for the pancreas by averaging the attenuations from three 1-cm² regions within the pancreas (head, body, and tail). These measurements were executed meticulously, with the exclusion of the pancreatic duct and margins from the selected areas. Similarly, the CT attenuation for the liver was ascertained by calculating the average CT attenuations from three 1-cm² regions within the liver (anterior, posterior, and lateral). For skeletal muscle fat, we measured the CT attenuation of the psoas major muscle at the L3 level. The CT attenuations of the spleen and renal parenchyma were determined by calculating the average CT attenuations of three 1-cm² regions of each organ (upper, middle, and lower). Our previous study regarding interrater reliability showed an intraclass correlation coefficient of 0.86 to 0.98 (7). The images were analyzed using the Aquarius Net Viewer (TeraRecon, Inc., Tokyo, Japan). Renal sinus fat accumulation was measured volumetrically using the Aquarius iNtuition (TeraRecon, Inc.). Adipose tissue was identified using pixel density measured in Hounsfield units (HU), with a specified range of −195 to −45 HU for analysis (8). We used the Synapse Vincent system (Fujifilm, Inc., Tokyo, Japan) to measure the visceral fat area (VFA) and subcutaneous fat area at the navel level. All CT scanning was performed with a slice thickness of 5 mm.

According to the previously reported method (5), the attenuations of the pancreas, liver, spleen, muscle, and renal parenchyma were inverted so that higher values corresponded to more fat. We examined the relationships among visceral fat, subcutaneous fat, and intra- and periorgan fats using the partial correlation coefficient, corrected for age, sex, and BMI. We also performed subgroup analyses separately for men and women. We then divided the participants into the visceral fat accumulation group (VFA ≥100 cm²) and the nonvisceral fat accumulation group (VFA <100 cm²), according to the criteria validated in Japanese (9), performed an ANCOVA adjusting for BMI, and investigated the relationship between the presence of visceral fat accumulation and intra- and periorgan fat accumulations. We conducted statistical analyses using R software (version 4.2.2; https://www.r-project.org/), and statistical significance was determined at a two-sided P value <0.05.

The data sets analyzed in the current study are available from the corresponding author upon reasonable request. No applicable resources were generated or analyzed during the current study.

Ultimately, 84 patients were enrolled (Supplementary Fig. 1). Characteristics of the patients are listed in Table 1. Visceral fat was significantly positively correlated with liver fat, renal sinus fat, and skeletal muscle fat (r = 0.29 and P = 0.007, r = 0.38 and P < 0.001, and r = 0.25 and P = 0.02, respectively), whereas visceral fat and subcutaneous fat were significantly negatively correlated (r = −0.42 and P < 0.001) (Fig. 1). Whereas visceral fat was positively correlated with all intra- and periorgan fats, subcutaneous fat was negatively correlated with all intra- and periorgan fats (Supplementary Fig. 2). In subgroup analysis, men had significantly higher levels of liver and visceral fats, whereas women had significantly higher levels of subcutaneous fat (Supplementary Table 1). The significant associations between each fat remained consistent when we analyzed the correlations separately in men and women (Supplementary Fig. 3).

In addition, the results of the covariance analysis showed that intra- and periorgan fat accumulations in the pancreas, liver, renal sinus, and skeletal muscle were significantly greater in participants with excessive visceral fat accumulation than in those without excessive visceral fat accumulation (Fig. 2).

This study revealed that subcutaneous and visceral fats had contrasting associations with intra- and periorgan fat accumulations, after adjustment for BMI. In partial correlations, subcutaneous fat was inversely correlated with both visceral fat and intra- and periorgan fats, whereas visceral fat was positively correlated with all intra- and periorgan fat accumulations. These correlations suggest that subcutaneous fat acts protectively against accumulations of visceral fat and intra- and periorgan fats. Although there have been several previous studies reporting that increased visceral fat is associated with accumulations of fat in the liver (10) and pancreas (11), to our knowledge, this is the first study to report the comprehensive interrelationships of intra- and periorgan fat accumulations, particularly the negative association of subcutaneous fat accumulation with visceral fat and intra- and periorgan fat accumulations.

Subcutaneous fat represents a proper expansion of adipocytes and can therefore be considered a protective fat depot (12). Excess visceral fat deposition is speculated to occur because of the relative dysfunction of subcutaneous adipose tissue (13). A previous study reported that compared with individuals with more subcutaneous fat and more visceral fat, those with less subcutaneous fat and more visceral fat had a higher prevalence of hypertriglyceridemia (14). Individuals with less subcutaneous fat and more visceral fat may lack sufficient adipocytes and have limited capacity to store fat in adipose tissue, resulting in intra- and periorgan fat storage (14).

By comparing the participants with and without excessive visceral fat accumulation, we showed that visceral fat was significantly related to intra- and periorgan fat accumulations (pancreas, liver, skeletal muscle, and renal sinus) after adjusting for BMI. Because BMI is more correlated with subcutaneous fat than with visceral fat (9), it seems more appropriate to refer to visceral fat content rather than BMI to assess intra- and periorgan fat accumulations. In this analysis, skeletal muscle fat showed a different direction in relation to BMI than other intra- and periorgan fats. This might be because, especially in elderly individuals, a lower BMI can enhance muscle loss and sarcopenia, leading to an increase in skeletal muscle fat.

In the current study, there was no relationship between renal parenchyma fat, spleen fat, and visceral fat. The renal parenchyma accumulates an extremely small amount of fat compared with the inside of the renal sinus, and the spleen is an organ often used as a control, such as in the liver-spleen contrast, and is considered to be an organ in which intra- and periorgan fats are unlikely to accumulate.

In the subgroup analysis separated by sex, we found that men had significantly higher levels of liver fat, renal sinus fat, and visceral fat, whereas women had significantly higher levels of subcutaneous fat. These results are consistent with previous reports showing that men accumulate more liver fat (15) and renal sinus fat (16).

The strength of the current study is its analysis of a comprehensive set of fat compartments and its focus on partial correlations rather than simple two-way correlations, because fat compartments are highly interrelated. Our approach allowed assessment of the independent correlation of each fat and revealed the biologically inverse correlation between subcutaneous and visceral fat.

There are several limitations in this study that should be noted. First, the study group comprised a small number of hospitalized Asian patients who underwent CT scans. Therefore, the associations observed in the current study may not necessarily apply to other ethnic groups or individuals who are not hospitalized. Further investigation with larger sample sizes will be required. Second, there was no histologic verification of intra- and periorgan fats in our study. However, the assessment technique used in this study has been validated in a prior study, revealing significant correlations between CT attenuation and histologically determined fat levels (6). Third, the CT scanners used in this study were not uniform, and scans were obtained under varying imaging conditions with different tube voltages. Fourth, this study measured subcutaneous trunk fat and did not measure gluteal/femoral fat. Gluteal/femoral fat has been reported to have different lipolytic properties compared with subcutaneous trunk adipose tissue, potentially having a more protective effect on the human body. Future investigations using midthigh CT scans will be necessary.

In conclusion, we have demonstrated that intra- and periorgan fat accumulations in each organ show a positive correlation with visceral fat accumulation and a negative correlation with subcutaneous fat accumulation, independent of BMI.

Acknowledgments. The authors thank the staff of TeraRecon, Inc., Tokyo, Japan, for explaining how to measure renal sinus fat.

Funding. This study was supported by the Grants-in-Aid for Scientific Research program of the Japan Society for the Promotion of Science (grant 21K17660).

Duality of Interest. M.Y.B. and H.O. belong to the Department of Lifestyle Medicine, which is a sponsored course endowed by Kubara Honke Co., Ltd. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. K.M. and M.Y.B. conceived and designed the study, performed statistical analysis, and drafted the manuscript. K.M., M.Y.B., T.K., S.K., A.N., R.T., T.H., H.O., C.I., Y.H., Y.F., and J.K. interpreted the data. J.K. and I.S. critically revised the manuscript. All authors participated in the writing process of the manuscript and gave their final approval of both the submitted and published versions. M.Y.B. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation. Parts of this study were presented at the 43rd Japan Society for the Study of Obesity, Okinawa, Japan, 2–3 December 2022.