CE / CME
Physician Assistants/Physician Associates: 0.50 AAPA Category 1 CME credit
Nurses: 0.50 Nursing contact hour
Physicians: maximum of 0.50 AMA PRA Category 1 Credit™
Released: December 12, 2023
Expiration: December 11, 2024
Adipose Tissue Metabolism
Adipose tissue was once thought of as an inert repository for extra energy in our body, in the form of triglycerides. However, our understanding of this organ has evolved with the identification of many signaling molecules and metabolites that are released by healthy adipose tissue, which are listed on the slide.1 These molecules and metabolites, especially free fatty acids and adiponectin, play major roles in governing energy expenditure, appetite, and insulin sensitivity.
Adipose Tissue as a Metabolic Organ: Fatty Acids
Key to understanding MASH is the role of insulin in suppressing the breakdown of triglycerides in fat cells that results in release of fatty acids, also known as adipose tissue lipolysis.2
After a meal, insulin usually suppresses lipolysis. However, insulin resistance at the adipose tissue level results in continued release of fatty acids into the blood, to eventually be taken up by the liver.1
Adipose Tissue as a Metabolic Organ: Adiponectin
Adiponectin is another important product of adipose tissue, and it is often used as a marker for efficacy in clinical trials of drugs for MASH.1
Compared with healthy individuals, expression of adiponectin is more than 50% lower in patients with MASH.3 Effective therapies are often associated with increases in serum adiponectin, suggesting improvement in adipose tissue health.4
Adipose Tissue as a Metabolic Organ: Adiponectin
In brief, adiponectin is involved with insulin signaling across many tissues, including the liver.5 When adiponectin is secreted from healthy adipose tissue, it decreases gluconeogenesis, triglycerides, lipogenesis, and ceramides, one of the mediators of MASH pathogenesis.6
Adiponectin also plays a role in regulation of neuroplasticity through crosstalk with insulin signaling, with beneficial effects on neuron growth and stress. While neuroplasticity is highlighted here, adiponectin crosstalk with insulin signaling occurs across many other tissues, including the liver.5
Adipose Tissue as a Metabolic Organ: Plasma Adiponectin and Metabolic Disease
This study demonstrates the association between plasma adiponectin and severity of metabolic disease.9
Before treatment, the investigators compared the levels of plasma adiponectin in patients with MASH to healthy controls. They found that healthy controls with normal glucose tolerance had the highest plasma adiponectin, followed by healthy controls with impaired glucose tolerance. However, patients with MASH had much less adiponectin, whereas patients with MASH and type 2 diabetes had even lower adiponectin concentrations.
Patients with MASH then received either placebo or pioglitazone, which is known to promote expansion of healthy adipose tissue and reduce release of fatty acids and insulin resistance. Treatment with pioglitazone increased both hepatic insulin and plasma adiponectin, although not to the level of healthy controls.
These results suggest that pioglitazone may improve MASH, potentially through increased release of adiponectin.
Stressed Adipose Tissue
What causes decreases in adiponectin and metabolic disease? The answer is stressed adipose tissue, which can be the result of overexpansion because of an excess of nutrients.1
Stressed Adipose Tissue
Excess food consumption expands adipose tissue.1 Healthy adipose tissue expansion occurs within limits that vary from person to person, manifesting as some weight gain with no metabolic disease yet.
Stressed Adipose Tissue
However, if the adipose tissue expands too much, what happens is metabolically unhealthy obesity, resulting in insulin resistance and metabolic syndrome, the inappropriate release of fatty acids from stressed adipose tissue, the release of inflammatory cytokines, and a decrease in adiponectin.1 Reduced plasma adiponectin is a hallmark of stressed and dysfunctional adipose tissue.
Stressed Adipose Tissue
Another important aspect of this is lipodystrophy.1 Every individual has a limit on how much their adipose can expand. It varies from person to person, which is why there is the concept of metabolically healthy obesity. Some people’s adipose tissue is able to expand and keep expanding, whereas others’ adipose tissue can only expand a little bit before it becomes stressed. An extreme example of that is people with lipodystrophy, whose adipose tissue cannot expand.
The inability to expand adipose tissue leads to metabolic consequences even in the absence of obesity: Individuals with lipodystrophy have no obesity but experience all the metabolic effects, including decreased adiponectin, contributing to metabolic disease.
Genetic Factors in MASLD/MASH
In addition to outside factors, such as excess nutrition and lipodystrophy, there are genetic factors that may contribute to MASH.8 Some of the major polymorphisms that have been recognized to predispose to vs protect an individual from NASH are listed here.
Genetics vs Role of Metabolic Comorbidities
What is the role of genes vs metabolic disease in MASH?
A study by De Vincentis and colleagues9 evaluated the association between the HR of liver-related events and a polygenic risk score (PRS-HFC, based on genetic variants in PNPLA3, TM6SF2, MBOAT7, and GCKR) that predicts hepatic fat content. Analyses were further stratified according to the presence of metabolic risk factors.
In patients with diabetes and obesity, a higher PRS-HFC was associated with increased risk of liver-related events. However, in patients with no metabolic risk factors, there was no association between liver-related events and polygenic risk score.
These data suggest that there is an interaction between metabolic disease and genetics: The genes alone, or at least these 4 genes, do not explain everything. Variants in these 4 genes increased risk for liver-related events in the presence of other metabolic risk factors, but alone were not major contributors.
MASH Pathogenesis: Role of Metabolic Comorbidities
Let’s consider the relationship between fatty liver disease and all the other manifestations of metabolic disease. We have covered what happens when the nutrition supply exceeds the adipose storage capacity, and how that contributes to MASLD.10
Of course, there are also genetic, dietary, and environmental contributors to MASLD.10
MASH Pathogenesis: Role of Metabolic Comorbidities
Many studies maintain that there is a correlation between MASLD and insulin resistance as well as many other aspects of the metabolic syndrome.10-13 However, I am going to argue against that.
MASH Pathogenesis: Role of Metabolic Comorbidities
These studies are epidemiologic and cannot show causality, and mechanistic studies don’t support these claims.
For example, there are variants of ApoB or PFLA3 that are associated with increased fat but not with insulin resistance. Thus, fat in the liver does not cause insulin resistance when you look at it in light of this evidence.10,11
MASH Pathogenesis: Role of Metabolic Comorbidities
It is more accurate to say that when the fat supply exceeds adipose storage capacity, it inflicts stress on adipose tissue, which leads to insulin resistance and increased circulation of fatty acids, becoming the cause of all these other aspects of metabolic disease.10,11 This is what the mechanistic studies show. It is not the other way around.
MASH Pathogenesis: Role of Metabolic Comorbidities
What does this mean for therapy? Until now, specific treatments have been developed to target each of these components of metabolic disease: hypertension, hyperglycemia, lipid glycemia, type 2 diabetes, and macrovascular disease to some extent.
MASH Pathogenesis: Role of Metabolic Comorbidities
Perhaps it would be better if we had a metabolic therapy that addresses the underlying issues of insulin resistance—what is happening in the adipose tissue—similar to how pioglitazone promotes expansion of healthy adipose tissue.9
The Pathogenic Relationship Between Diabetes and MASH
Supporting the idea of treating underlying insulin resistance, although there are no drugs specifically approved for treatment of MASH, some medications for type 2 diabetes have been proven effective for MASH management. In particular, glucagon-like peptide-1 (GLP-1) receptor agonists have been used to manage both type 2 diabetes and MASH.
This works because pathogenesis of MASH and type 2 diabetes are closely linked: increased adiposity—and adipose tissue insulin resistance and dysfunction—results in increased free fatty acids in the blood.14 The increase in free fatty acids results in lipotoxicity, which is associated with increased insulin resistance in the periphery.
Role of GLP-1 in MASH Pathogenesis
The positive effects of using a GLP-1 receptor agonist to treat MASH are likely multifaceted, a result of cumulative improvements on weight, insulin resistance, and metabolic phenotypes.15,16
Native GLP-1 lowers blood glucose by inducing insulin secretion and reducing glucagon secretion from the pancreas. In the liver and muscle, this increases insulin sensitivity.
GLP-1 receptor agonists used to treat MASH work in much the same way, by improving hepatic and global insulin sensitivity and, in turn, reducing lipotoxicity and inflammation.
MASH Pathogenesis Summary
In terms of pathogenesis, the epidemiologic data suggest a complex bidirectional relationship between MASH and type 2 diabetes, although the mechanistic data do not support that. Rather, the mechanistic studies suggest that sick and stressed adipose tissue leads to insulin resistance, which leads to diabetes and MASH.
Genetic contributions can predispose individuals to MASH but are not major contributors alone.
From this perspective, therapies that address the underlying metabolic disease may have the greatest benefit. This may explain why many investigational MASH treatments that instead have targeted inflammatory pathways and cell death pathways have been ineffective.
To slow MASH down, one needs to slow the stress in the adipose tissue that causes inflammation. Perhaps combination therapy for MASH should address the inflammatory and the metabolic factors contributing to it.
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