The Hidden Fat in Your Muscles: Understanding Intermuscular Adipose Tissue

According to a review published in Frontiers in Endocrinology, intermuscular adipose tissue (IMAT) is a type of fat hidden within and between muscles. Unlike the more familiar subcutaneous fat, IMAT is strongly linked to insulin resistance, muscle dysfunction, and increased risk of metabolic diseases like type 2 diabetes. It forms from various cell types, including muscle stem cells and fat progenitor cells. IMAT's negative effects include promoting inflammation, disrupting muscle function, and contributing to insulin resistance. However, there's potential for IMAT to be transformed into beneficial brown fat, which burns energy. While research is ongoing, potential strategies to combat IMAT include inhibiting its formation, promoting its transformation into brown fat, reducing inflammation, and optimizing muscle-fat communication. Ultimately, understanding IMAT is crucial to developing effective treatments for obesity and related metabolic disorders.

Key points

• Hidden Fat: IMAT is fat located within and between muscles, often overlooked compared to subcutaneous fat.

• Metabolic Impact: IMAT is strongly linked to insulin resistance, muscle dysfunction, and an increased risk of metabolic diseases.

• Multiple Origins: IMAT can develop from various cell types, including muscle stem cells and fat progenitor cells.

• Negative Effects: IMAT contributes to inflammation, disrupts muscle function, and is associated with ectopic lipid storage.

• Potential for Good: Under certain conditions, IMAT can be transformed into beneficial brown fat, which burns energy.

• Therapeutic Promise: Research is exploring ways to inhibit IMAT formation, promote brown fat development, and reduce its negative impacts.

When we think about body fat, we typically picture the jiggly stuff under our skin or surrounding our organs. But there's another type of fat that's been getting increased attention from researchers in recent years - intermuscular adipose tissue, or IMAT for short. This "hidden fat" that accumulates between and within our muscles may play a bigger role in metabolic health than previously realized.

What exactly is IMAT?

Intermuscular adipose tissue refers to fat deposits that develop between muscle fibers or adjacent muscle groups. It's distinct from the fat stored within muscle cells themselves (called intramyocellular lipids). As obesity progresses, IMAT tends to expand along with the more visible subcutaneous and visceral fat depots. While IMAT accounts for a relatively small percentage of total body fat, its location within skeletal muscle tissue gives it an outsized influence on metabolism and muscle function. Numerous studies have linked higher levels of IMAT to insulin resistance, impaired muscle performance, and increased risk of metabolic diseases like type 2 diabetes. The good news is that as we learn more about the origins and regulation of IMAT, we're uncovering potential ways to target this problematic fat depot. Let's dive into what the latest research reveals about IMAT and its implications for health and disease.

Where does IMAT come from?

One of the key questions researchers have been investigating is the cellular origins of IMAT. Unlike typical fat tissue that develops from adipocyte precursor cells, IMAT appears to have multiple potential sources:

1. Muscle satellite cells: These muscle stem cells can differentiate into fat cells under certain conditions, especially when lacking key myogenic factors.

2. Fibro/adipogenic progenitors (FAPs): A population of mesenchymal progenitor cells residing in muscle tissue that can become either fibroblasts or adipocytes.

3. Other muscle-resident progenitor cells: Various other cell populations within muscle, including some myeloid-derived cells, have shown adipogenic potential.

4. Adipose tissue-derived progenitors: Fat progenitor cells from other depots may migrate into muscle tissue and contribute to IMAT formation.

This diversity of cellular origins likely contributes to the heterogeneity seen in IMAT. Some intermuscular adipocytes resemble classical white fat cells, while others express markers of brown/beige adipocytes. The specific characteristics of IMAT in different contexts may influence its metabolic effects.

Regulating IMAT development

The accumulation of IMAT is controlled by a complex network of molecular signals and environmental factors. Some key regulators that have been identified include:

Transcription factors: The usual suspects involved in adipogenesis, like PPARγ and C/EBP proteins, play important roles. Members of the Krüppel-like factor (KLF) family appear to be particularly influential in IMAT formation.

Signaling pathways: The Wnt, Hedgehog, and Notch signaling cascades help control the balance between myogenesis and adipogenesis in muscle progenitor cells.

Myokines: Factors secreted by muscle fibers, including myostatin, IL-15, and irisin, can modulate IMAT development.

Muscle fiber type: Slow-twitch oxidative muscle fibers seem more permissive to IMAT formation compared to fast-twitch glycolytic fibers.

Nutritional factors: Vitamins A and D, as well as minerals like copper, zinc, and iron, influence IMAT through various mechanisms.

Inflammation: Obesity-associated inflammation promotes IMAT expansion and alters its properties.

This multifaceted regulation allows for precise control of IMAT under normal conditions, but also creates multiple points where dysregulation can occur in disease states.

IMAT's impact on metabolism

The infiltration of fat into skeletal muscle tissue has several detrimental effects on whole-body metabolism:

Insulin resistance: IMAT is strongly associated with reduced insulin sensitivity, even more so than other fat depots. It may impair insulin signaling both locally in muscle and systemically.

Inflammation: IMAT contains inflammatory immune cells and secretes pro-inflammatory factors that contribute to chronic low-grade inflammation.

Muscle dysfunction: Excessive IMAT accumulation is linked to reduced muscle strength, impaired regeneration, and accelerated sarcopenia in aging.

Altered muscle-fat crosstalk: The close proximity of IMAT to muscle fibers disrupts normal paracrine signaling between these tissues.

Ectopic lipid storage: IMAT represents an abnormal site of lipid deposition that may have toxic effects on surrounding cells.

These metabolic perturbations help explain why IMAT is emerging as an important risk factor for conditions like type 2 diabetes, cardiovascular disease, and mobility limitations in older adults.

The browning potential of IMAT

While IMAT is generally viewed as metabolically harmful, some intriguing research suggests it may have a silver lining. Studies in mice have found that under certain conditions, IMAT can take on characteristics of brown or beige fat—the "good" type of fat that burns energy and improves metabolism. For example, some mouse strains prone to obesity resistance show higher levels of UCP1-expressing brown-like adipocytes within their IMAT. And transplanting brown fat progenitors into skeletal muscle leads to the formation of functional brown fat that increases energy expenditure. In humans, a reservoir of brown adipocyte progenitors has been identified in skeletal muscle tissue. These cells can differentiate into UCP1-positive brown adipocytes when stimulated appropriately. This raises the tantalizing possibility of converting harmful white IMAT into beneficial brown fat as a therapeutic strategy.

However, major questions remain about the browning capacity of human IMAT and whether it can be harnessed effectively. Most human IMAT still appears to resemble white adipose tissue metabolically. More research is needed to determine if promoting intermuscular brown fat is a viable approach for improving metabolic health.

Potential interventions targeting IMAT

As our understanding of IMAT biology grows, several promising avenues for therapeutic intervention are emerging:

Inhibiting IMAT formation: Strategies to block the proliferation or adipogenic differentiation of muscle-resident progenitor cells could prevent excessive IMAT accumulation. This might involve modulating key signaling pathways or delivering targeted inhibitors to FAPs.

Promoting brown/beige IMAT: Stimulating the development of thermogenic adipocytes within the muscle, potentially through PPARγ agonists or other browning agents, may improve the metabolic impact of IMAT.

Enhancing muscle-fat crosstalk: Optimizing the secretion of beneficial myokines and adipokines could help maintain a healthier balance between muscle and fat tissues.

Reducing inflammation: Since inflammation drives many of IMAT's negative effects, anti-inflammatory approaches may be beneficial. This could include targeting specific inflammatory mediators or immune cell populations within IMAT.

Modifying progenitor cell trafficking: Blocking the migration of adipocyte precursors from other depots into muscle tissue might limit IMAT expansion. The CXCR4/CXCL12 axis is one potential target here.

Exercise and nutrition: Physical activity and dietary interventions remain powerful tools for reducing IMAT and improving overall body composition. Resistance training may be particularly effective for combating IMAT accumulation.

Conclusion

Intermuscular adipose tissue represents a unique and metabolically important fat depot that deserves increased attention from researchers and clinicians alike. Its strategic location within skeletal muscle gives IMAT an outsized influence on whole-body metabolism and muscle function. While excessive IMAT accumulation clearly has detrimental health effects, the plasticity of this depot also presents intriguing therapeutic possibilities. By unraveling the complex biology of IMAT, from its diverse cellular origins to its multifaceted regulation - we're gaining valuable insights that may lead to more effective interventions for obesity and related conditions.

As the obesity epidemic continues to worsen globally, novel approaches for tackling ectopic fat deposition are urgently needed. IMAT-targeted therapies could potentially improve metabolic health while simultaneously enhancing muscle performance and mobility. While significant work remains to be done, research into this "hidden" fat depot is revealing promising new directions in the fight against metabolic disease.

The story of IMAT serves as a reminder that adipose tissue is far more complex and heterogeneous than once thought. By looking beyond classical fat depots, we're uncovering important new players in metabolic regulation. Further study of IMAT and other ectopic fat depots may yield additional surprises that reshape our understanding of obesity and its health consequences.

Journal Reference

Zhang, T., Li, J., Li, X., & Liu, Y. (2023). Intermuscular adipose tissue in obesity and related disorders: Cellular origins, biological characteristics and regulatory mechanisms. Frontiers in Endocrinology, 14. https://doi.org/10.3389/fendo.2023.1280853

Image credit:https://www.frontiersin.org/files/Articles/1150059/fendo-14-1150059-HTML/image_m/fendo-14-1150059-g003.jpg

Related

https://healthnewstrend.com/muscle-loss-and-fat-gain-unraveling-sarcopenic-obesity-in-older-adults

https://healthnewstrend.com/adiponectin-and-diabetes-unraveling-the-connection

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