Targeting liver fat to improve type 2 diabetes, the role of hepatokines

Cody Durrer modtog Diabetesforeningens forskningslegat 2023 på 600.000 kroner, der blev uddelt til Diabetesforeningens årsmøde i Odeon den 13. maj. 

Artiklen er skrevet af Cody Durrer, der skriver på engelsk.

Accordingly, the 2022 consensus report from the European Association for the Study of Diabetes, EASD, and the American Diabetes Association, ADA, put greater emphasis on weight loss as a target for hyperglycemia management. This is based, in part, on promising results following bariatric surgery and very-low calorie diets (VLCDs) wherein people living with T2D demonstrate normoglycemia with less (or in the absence of) glucose-lowering medications. Although a consensus on the definition of T2D remission has yet to be universally accepted, position statements published by prominent diabetes associations (e.g., ADA, IDF (International Diabetes Federation), EASD) emphasize three key points:

• Glycemia below diagnostic cutoffs for T2D
• No use of medications or ongoing therapy
• Persistence of the previous two points for an extended period of time.

Using this definition, the current body of evidence suggests that achieving weight loss of ~10% of body weight will, on average, typically lead to T2D remission. While the emphasis has been on weight loss, mechanistic studies suggest that depletion of ectopic fat in the liver and pancreas is central for this process of reversal (1).

The role of the liver

Accumulation of ectopic fat in the liver (i.e., hepatic steatosis) is highly prevalent in people living with T2D, with rates estimated to be ~60% (2).

Given the common pathogenic mechanisms of T2D and hepatic steatosis, it is unsurprising that the presence of either condition increases the risk of developing the other. Ectopic fat in the liver leads to hepatic insulin resistance and subsequent elevati- ons in fasting glucose and very-low-density lipoprotein (VLDL) cholesterol export. These conditions result in hyperglycemia and hyperlipidemia leading to pancreatic beta-cell dysfunction and reduced insulin secretion. Together, these defects represent the main underlying characteristics of T2D pathophysiology and emphasize the importance of the liver in disease progression.

Beyond blood glucose and lipids

In addition to directly impacting glycemia and lipidemia, hepatic steatosis is also accompanied by the aberrant secretion of signaling proteins, termed “hepatokines”, from the liver (3) which represent another causal link between hepatic steatosis and T2D in tissues throughout the body. The presence of hepatic steatosis and T2D is associated with increased secretion of hepatokines that are detrimental for normal metabolism (e.g., cause inflammation, insulin resistance, and glucose intolerance) and decreased secretion/action of hepatokines that are considered beneficial.

Among the variety of hepatokines that are dysregulated in T2D and hepatic steatosis are fibroblast growth factor 21 (FGF21) and fetuin-A (3,4). These hepatokines are particularly interesting because they are thought to influence the liver-adipose tissue axis and affect adiponectin secretion (5,6). The primary target for FGF21 is the adipose tissue, where it induces secretion of the insulin sensitizing hormone adiponectin (5). Although FGF21 secretion is elevated in T2D and hepatic steatosis, there is evidence of lower receptor/co-receptor expression on the adipocytes themselves which has given rise to the concept of FGF21 resistance (7,8). This is supported by the fact that adiponectin secretion is impaired in people with T2D (9). In mice, exercise training restores FGF21 signaling and subsequent increases in circulating adiponectin levels (7); however, this effect has not yet been tested in humans. FGF21 secretion can be induced by acute exercise, but this effect is absent in T2D (10). Higher exercise intensity induces a larger FGF21 response in healthy participants, but it is unknown whether this translates to T2D. Fetuin-A is also released by the liver and elevated in T2D. It is known to impair adiponectin secretion and cause inflammation (6). Although the aberrant secretion of these hepatokines is correlated with hepatic steatosis, it is currently unknown whether depletion of hepatic steatosis will ameliorate this effect and restore normal liver-adipose tissue axis function. Furthermore, while FGF21 and fetuin-A are currently considered the most important hepatokines for the liver-adipose tissue axis, research on all hepatokines in the context of metabolic disease remains drastically understudied.

When hepatic steatosis is combined with expansion of subcutaneous and visceral adiposity (and concurrent adipose tissue insulin resistance), the development of hepatic steatosis is accelerated due to further increased exposure to elevated circulating lipids and blood glucose. Together, this detrimental liver-adipose tissue axis feeds back to worsen itself and exacerbate the issues mentioned above. 

Body weight vs. Liver fat

While there is evidence to support strategies such as VLCDs and bariatric surgery for improving glycemia, beta-cell function, and reducing medication burden, the effect of depleting liver fat on pancreatic fat, lipid profile, and hepatokine secretion/function is unclear. It has been reported that bariatric surgery improves serum lipids, but the role of hepatic fat reduction per se is unknown and findings are limited to traditional measures of cholesterol (e.g., LDL-C, total cholesterol). It is now known that these parameters do not provide a full picture of cardiovascular risk when compared to the addition of apolipoprotein levels and lipoprotein particle size and concentration (11). Furthermore, the common use of semi-quantitative ultrasound measurement of hepatic fat has limited previous studies in providing an accurate assessment of its effect on other outcomes. Therefore, to accurately determine any potential reduction in cardiovascular disease risk conferred by reducing hepatic steatosis, more indepth studies are needed.

While T2D affects many tissues throughout the body, the steatotic liver lies at the center of hyperglycemia, hyperlipidemia, and metabolic dysfunction in other tissues via hepatokine signaling. For these reasons, the liver represents an optimal target to treat the underlying drivers of the disease.

The Project

With this in mind, the aim of this project is to uncover the role of liver fat and exercise intensity in the secretion and signaling of hepatokines in the adipose tissue. At the same time, we are also investigating the effect of long-term calorie restriction and exercise on the causes of type 2 diabetes. Specifically, Part 1 of the project will investigate exercise-induced hepatokine secretion and signaling in adipose tissue and determine whether this is affected by hepatic fat depletion and by different exercise intensities. Exercise intensity and the level of hepatic steatosis are both thought to be moderators of exercise-induced hepatokine release. The study will also perform a more in-depth analysis of blood lipids to better assess changes related to cardiovascular disease risk. Part 2 of the project will look more broadly at hepatokine secretion and signaling in adipose tissue following longer term diet-induced weight loss, either combined with exercise or alone. Taken together, this project will help to isolate the effects of hepatic fat depletion per se from weight loss and uncover an important disease process in T2D. The proposed research utilizes both dietary and exercise interventions in two different contexts: 1) As stimuli to investigate the underlying pathophysiology of T2D; 2) as potential therapies for T2D. As such, the results of the proposed research add to the understanding of the disease while simultaneously providing evidence-based advice for people with T2D.

It has become increasingly clear that the dysfunctional steatotic liver is a central and modifiable factor in T2D pathophysiology. This is both due to its direct effect of driving hyperglycemia and hyperlipidemia as well as its indirect effect of disrupting function of other tissues throughout the body via hepatokine signaling. Our goal is that by using diet and exercise as models to investigate this pathophysiological process, we will better understand the role of hepatokines in the broader picture of type 2 diabetes, while identifying diet and exercise-based strategies to alleviate the underlying causes of the disease. We hope that this research will lead to more effective T2D therapy, encompassing the optimal combination of diet, exercise, and pharmacological treatments to target the underlying disease drivers.

Keywords: Type 2-diabetes. Hepatic steatosis. Liver fat. Hepatokines. Weight-loss. Acute exercise. Exercise training.

Interessekonflikter: No conflicts of interest.