In this study, we analyzed changes in hepatokines and the metabolic effects of LSG in Japanese patients with severe obesity. The initial SeP levels correlated negatively with the VFA + SFA, whereas the initial LECT2 levels correlated positively with body weight, LV, histopathological liver steatosis, and the total NAFLD activity score. Furthermore, changes in LECT2 were negatively correlated with %TWL and changes in both SFA and VFA. The changes in SeP were also correlated with the changes in HbA1c and II. Moreover, SeP and LECT2 could predict T2D and NASH, respectively, in the severely obese Japanese patients.

Studies have identified more than 20 hepatokines, some of which play a key role in promoting metabolic syndrome, including T2D and NAFLD. Fetuin-A, the most widely studied hepatokine in humans, acts as a chemoattractant for macrophages, thereby increasing the expression of inflammatory cytokines. These inflammatory cytokines contribute to T2D and NAFLD [14]. Moreover, circulating fetuin-A inhibits glucose uptake by interfering with the translocation activity of glucose transporter type 4 [14]. Angioprotein-like protein 8 (ANGPTL8) is expressed primarily in liver and visceral adipocytes and associated with NASH by promoting various inflammatory pathways [15]. Fibrinogen-like protein 1 is also synthesized mainly in parenchymal hepatocytes and involved in conditions such as liver regeneration, immune activation, glucose and lipid metabolism [16]. In addition to SeP and LECT2, these hepatokines and metabolic disorders are complexly intertwined; therefore, the measurement and activity of hepatokines may help to identify a deeper mechanism of accelerating metabolic disorders in patients with severe obesity.

Metformin is commonly used as an antidiabetic agent and provides clear benefits in promoting glucose metabolism and preventing diabetic complications. It has been shown to act via a mechanism dependent on adenosine-monophosphate-activated protein kinase (AMPK), which includes the suppression of hepatic glucogenesis. We demonstrated previously that metformin suppresses the production of insulin-resistance-inducing SeP by activating AMPK and, subsequently, inactivating FoxO3a in the liver without directly stimulating pancreatic β-cells [17]. Through these mechanisms, metformin administration at the baseline might suppress the elevation of SeP levels; therefore, the true increase in SeP was negated despite the acute insulin resistance caused by severe obesity. In the current study, 10 of the 15 patients with T2D were given metformin at their baseline, and the initial SeP levels were significantly lower in these patients than in the patients not given metformin (3.5 μg/mL vs. 4.1 μg/mL, p = 0.023). On the other hand, no significant changes in SeP levels were observed 1 year after LSG. Most patients could stop taking metformin at the 1-year-post-LSG mark, presenting a high remission rate for T2D; thus, the participants’ SeP levels 1 year post-LSG were close to their true value.

The present study illustrated the positive correlation among initial LECT2 levels, body weight, and LV. Additionally, weight loss effects such as changes in %TWL and fat areas also correlated with changes in LECT2. These results suggest that LECT2 is a promising marker for the weight loss effects of MS. We identified a negative correlation only between LECT2 and %TWL, in contrast with the fat areas. This result can be explained by the fact that the body weight loss effect is brought about not only by fat reduction but also by muscle catabolism after LSG. However, we did not evaluate muscle catabolism and skeletal muscle volume in this study. Another clinical study measuring both LECT2 and skeletal muscle volume by bioelectrical impedance analysis is needed to clarify the true relationship between LECT2 and %TWL.

The new concept of metabolic-dysfunction-associated fatty liver disease (MAFLD) has been proposed by international expert panels [18]. Severely obese patients should be diagnosed with MAFLD without imaging modalities or liver biopsies, along with the definition and interpretation of MAFLD. We found previously that about 70% of patients with severe obesity presented with NASH using intraoperative liver biopsies and that the severity of T2D prevalence is closely related to the progression of hepatocyte ballooning and liver fibrosis [19, 20]. Based on these findings, we conclude that NASH in severely obese patients can be automatically included in MAFLD, and it is currently considered a very important targeted MS disease [21]. We reported recently that the hepatic expression of LECT2 is upregulated in association with the inflammatory signature in human liver tissues [8]. Furthermore, the elevation of LECT2 levels activates the pathway from TGF-β-activated kinase 1-binding protein and mitogen-activated protein kinase 4 to the c-Jun N-terminal kinase (JNK) induced by lipopolysaccharides as an adjuvant and shifts residual liver macrophages to the M1-like phenotype, contributing to the development of liver inflammation [22, 23]. Li et al. also demonstrated that thrombospondin-1 (THBS-1) is a reliable biomarker of NASH, advances liver fibrosis, and is closely related to the JNK pathway [23]. These duplicated stimulations of liver macrophages may rapidly accelerate liver inflammation. From the current MAFLD algorithm, patients undergoing MS are automatically diagnosed as having MAFLD from severe obesity and/or prevalence of T2D. On the other hand, LECT2 secretion from visceral adipose tissue may have an effect on the onset and progress of metabolic syndrome including NASH [24]. Yoo et al. demonstrated that circulating LECT2 levels were significantly associated with NAFLD (p < 0.001) and metabolic syndrome (p = 0.016) caused by mediating dyslipidemia and abdominal obesity [25]. On the other hand, LECT2 levels do not correctly reflect the inflammatory change and liver fibrosis required for the diagnosis of NASH. We can apply circulating LECT2 levels as a predictive marker of metabolic syndrome on the basis of previous relationships between LECT2 and MAFLD. Further detailed evaluations are warranted to apply LECT2 for distinguishing NASH in patients with MAFLD.

Lipid metabolism is another mechanism of progression from simple steatosis to NASH. First, fatty acid accumulation in hepatocytes causes mitochondrial damage that further aggravates fatty acid accumulation and results in liver inflammation [8, 22]. Second, arachidonic acid metabolism is accelerated by the overproduction of proinflammatory eicosanoids; then, prostaglandins, thromboxanes, and leukotrienes are produced by cyclooxygenase. We also demonstrated that a specific phosphatidylcholine (18:1e_20:4) involved in the arachidonic acid cascade changed significantly after LSG in severely obese Japanese patients with NASH [26]. Based on these results, further studies on SeP and LECT2 are needed to clarify the relationship between hepatokines and lipid metabolism.

Kim et al. demonstrated recently that adipose tissue LECT2 mRNA and serum LECT2 were higher in women with obesity and correlated significantly with parameters related to insulin resistance [24]. Moreover, immunochemical analysis of human tissues revealed that LECT2 is expressed in adipocytes [27]. Based on this background, comparing LECT2 mRNA and protein expression in both the liver and visceral fat tissue is mandatory to detect which is the dominant organ secreting LECT2. If both the liver and visceral fat tissue secrete LECT2 independently with the lipid accumulation of hepatocytes and visceral adipocytes, both T2D and NASH will ensue and worsen rapidly. Another study using human liver specimens and visceral adipocytes must be conducted to clarify this insight into patients with severe obesity. MS can be a strong therapeutic strategy to halt the overproduction of LECT2 if this insight is confirmed as the true phenomenon of metabolic syndrome.

When interpreting the results of the current study, some limitations must be considered. First, the number of patients we recruited was limited by the requirement for specific measuring kits for hepatokines. Second, the study itself involved only one institution and was retrospective, because a single institutional observational study might produce selection and confounding biases. Third, our results indicate only the early postoperative outcomes and changes associated with hepatokines. Long-term results of T2D remission and histopathological NASH improvement have received the most attention in the MS context; therefore, studying the long-term changes in hepatokines and the relationships between hepatokines and weight loss effects, metabolic parameters, and inflammatory parameters may yield new findings that could relate to another therapeutic target of these diseases [1, 19]. Ultimately, further studies with more participants and data from longer follow-up periods are warranted to evaluate the true effect of hepatokines on severely obese patients.

In conclusion, our study shows that hepatokines serve a crucial function in controlling obesity-related comorbidities such as T2D and NASH. In Japanese patients with both severe obesity and T2D, circulating levels of the diabetes-associated hepatokines, SeP, did not alter during the course of weight reduction, possibly biased by a reduction in glucose and insulin and metformin washout. However, the changes in SeP were correlated significantly with reductions in HbA1c and II after MS. On the other hand, circulating levels of the liver fat-associated hepatokines, LECT2, were closely correlated with the severity of NASH, including steatosis and inflammation. Reductions in LECT2 correlated significantly with reductions in weight and fat mass. These findings suggest the cause and consequence of hepatokines, contributing to the metabolic benefits of MS.