Understanding how the body processes fats is central to tackling obesity, type 2 diabetes, and fatty liver disease. Yet, traditional models often fail to capture the complexity of human lipid metabolism, which depends on the coordinated activity of organs like the liver, adipose tissue, pancreas, and muscle. Emerging technologies such as organoids for lipid metabolism and organ-on-chip platforms now make it possible to recreate these processes in vitro. In this article, we will first remind the role of metabolism-related organs and how they connect, then highlight new approaches and methodologies, from organoids to organ-on-chip, that are transforming disease modeling and drug discovery.
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Key Organs of Lipid Metabolism and Their Crosstalk in Disease
The body’s major metabolic organs, adipose tissue (fat), the liver, skeletal muscle, and the pancreas, each play distinct roles in lipid metabolism and energy balance. These organs are in constant communication via hormones, nutrients, and nerves to maintain homeostasis. When this multi-organ crosstalk functions properly, it enhances fat burning, limits fat accumulation, and keeps blood lipid levels in check. Conversely, when the network breaks down, as in obesity, the resulting imbalances lead to metabolic pathologies.
Adipose tissue is the primary energy reservoir, storing excess calories as triglycerides. In times of plenty, white adipose tissue expands to safely sequester fat and prevent lipids from flooding other organs. Far from being inert storage, fat is also an active endocrine organ: it releases signaling molecules called adipokines (like leptin and adiponectin) that help regulate appetite, insulin sensitivity, and inflammation. Under healthy conditions, leptin from fat signals the brain to reduce hunger and helps muscles and liver adjust fuel usage, while adiponectin boosts fatty acid oxidation in muscle and curbs glucose production in the liver. These hormonal signals ensure that lipids are stored and utilized efficiently. In obesity, however, adipose signaling is disrupted, chronically high leptin levels lead to leptin resistance (the brain and body stop responding), and adiponectin levels plummet. This results in unchecked appetite, reduced fat-burning in muscles, and higher fat buildup in the liver. The dysfunction of fat tissue thus directly contributes to conditions like insulin resistance and fatty liver disease. Indeed, excessive fat accumulation in the liver defines NAFLD, and this can progress to an inflammatory state called non-alcoholic steatohepatitis (NASH) with fibrosis (scarring of the liver) if metabolic stress persists.
The liver is a central hub of lipid metabolism. It manufactures, stores, and exports fats (e.g. cholesterol and triglycerides) and helps distribute energy throughout the body. The liver takes up free fatty acids from the circulation, for instance, after a high-fat meal or when released by adipose tissue during fasting. If the influx of fat overwhelms the liver’s capacity, fat begins to accumulate in liver cells (hepatocytes). This is the hallmark of non-alcoholic fatty liver disease (NAFLD), a condition now common in individuals with obesity and metabolic syndrome. NAFLD can further induce inflammation and damage (NASH), potentially progressing to liver fibrosis or cirrhosis. The liver also communicates with other organs by secreting its own hormones and factors. For example, it produces fibroblast growth factor 21 (FGF21) in response to metabolic stress, which can promote fat oxidation in adipose tissue and muscle. In metabolic disease, these inter-organ feedback loops are disrupted, an overburdened fatty liver not only fails to regulate blood lipids properly, but also sends out abnormal metabolic signals that can exacerbate whole-body insulin resistance and dyslipidemia.
Skeletal muscle plays a pivotal role as a consumer of lipids. Muscle fibers use fatty acids as a key fuel, especially during physical activity, and healthy muscle tissue helps clear fats and sugars from the bloodstream under insulin’s direction. There is a two-way conversation between muscle and fat. On one hand, adipose-derived hormones like leptin and adiponectin enhance muscle’s ability to oxidize fatty acids and take up glucose, keeping muscle insulin-sensitive. On the other hand, working muscles release myokines (muscle-secreted factors) that influence fat tissue. During exercise, for instance, muscles secrete molecules such as IL-6 and irisin that travel through the blood to adipose depots, prompting increased fat breakdown and the “browning” of white fat (i.e. white fat cells taking on features of heat-producing brown fat). This muscle-to-fat crosstalk boosts energy expenditure and can counteract obesity-related weight gain. In sedentary or obese states, however, muscle can become a victim of lipid overload: fat droplets accumulate within muscle fibers when caloric intake is chronically high, leading to insulin resistance in muscle. As muscles become less responsive to insulin, blood glucose levels rise, forcing the pancreas to work harder. The pancreas, through its insulin-producing β-cells, attempts to compensate for insulin resistance by secreting more insulin. Over time, this strain can cause β-cell dysfunction or failure, precipitating type 2 diabetes. Thus, ectopic fat in muscle and other tissues links obesity to diabetes by blunting insulin’s effects and overwhelming the pancreas.
Other organs and systems join this metabolic web as well. The brain (particularly the hypothalamus) senses adipose signals like leptin to control appetite and energy expenditure; when leptin resistance develops, the brain fails to curb appetite, contributing to further weight gain. The intestine is the gateway for dietary lipids, packaging fats into chylomicrons that are delivered to adipose tissue and liver. Gut-derived hormones (such as GLP-1) and even the gut microbiome can influence liver fat accumulation and systemic metabolism, forming a gut–liver axis implicated in NAFLD. Additionally, chronic inflammation arising from enlarged adipose depots in obesity acts as a common thread disrupting metabolic signaling. Pro-inflammatory cytokines (secreted by immune cells in fat and liver) can worsen insulin resistance and organ crosstalk, creating a vicious cycle of metabolic deterioration.
In summary, metabolic diseases are multi-organ in nature: an imbalance in one organ reverberates through others. Obesity illustrates this clearly: excessive adipose tissue alters hormone levels and free fatty acid release, which in turn fatten the liver, tax the pancreas, and reduce muscle insulin sensitivity, ultimately driving conditions like NAFLD and type 2 diabetes. Conversely, when the liver, fat, and muscle communicate properly, the body can efficiently handle lipids and maintain metabolic health(1,2). This intricate physiology is why researchers are keen to study organ crosstalk in the context of disease. Traditional cell cultures or animal models often fail to capture the human-specific interactions between, say, human liver and human fat tissue. As a result, scientists are turning to advanced in vitro systems to model these relationships. Organoids (3D mini-organs grown from stem cells) and organ-on-a-chip platforms (microfluidic devices simulating organ function) now make it possible to investigate human organ interactions under controlled conditions. In the following sections, we will see how single-organ models – including adipose tissue organoids and liver organoids on chips – are shedding light on metabolic disease mechanisms, and how multi-organ microphysiological models are being used to recreate the complex cross-talk of metabolic organs in the lab(3).
Organoids and Organ-on-Chip Models for Studying Lipid Metabolism
Organoids and organ-on-chip systems are powerful approaches to recreate human metabolism in vitro. Organoids, grown from stem or primary cells, self-organize into 3D structures that preserve tissue-specific cell types and metabolic programs, such as lipid storage in adipocytes or glucose release in hepatocytes. Organ-on-chip devices combine living cells with microfluidics to mimic blood flow, nutrient delivery, and tissue–tissue interfaces, enabling real-time readouts of lipid uptake, secretion, and hormonal signals. Their design overcomes many limitations of traditional cultures by allowing chronic exposure studies, spatial organization, and non-invasive sampling, making them particularly relevant for metabolic disease research.
Adipose tissue
Adipose tissue stores energy as triglycerides and releases free fatty acids during fasting, while also secreting adipokines that regulate appetite, insulin sensitivity, and inflammation. Dysregulated adipose function in obesity alters lipid release and systemic metabolism. To capture these processes, adipose-on-chip models culture human mature adipocytes under flow, maintaining their viability and functionality. For instance, Rogal et al. developed a white adipose tissue-on-chip that enabled real-time imaging of fatty acid uptake and quantification of glycerol and free fatty acid release in effluents, demonstrating both storage and mobilization functions of human fat tissue under controlled conditions(4). Similarly, Huff et al. optimized a fat-on-a-chip model for non-invasive monitoring, showing how adipocytes equilibrate droplet size within extracellular matrices and respond to insulin by increasing glucose uptake(5). These models illustrate how adipose tissue’s role in energy storage and release can be probed directly in human-derived platforms.
Liver
The liver orchestrates lipid synthesis, oxidation, and export, and is the central organ affected in non-alcoholic fatty liver disease (NAFLD). Liver-on-chip and liver organoid models replicate features of the sinusoid, cell diversity, and metabolic gradients. Freag et al. built a NASH-on-a-chip with hepatocytes, Kupffer, stellate, and endothelial cells, which developed hallmark features of disease (steatosis, inflammation, and fibrosis) under lipid overload, and responded to pharmacological treatment with reduced lipid accumulation(6). Gori et al. showed that microfluidic perfusion of fatty acids in a liver-on-chip sinusoid model resulted in gradual lipid accumulation with better cell viability than static cultures, more closely mirroring chronic steatosis(7). More recently, Igarashi et al. generated human hepatocyte organoids capable of long-term expansion and adult metabolic functions, including bile canalicular networks and zonated lipid metabolism, representing a powerful tool for studying both physiology and pathology(8).
Pancreas
Pancreatic β-cells secrete insulin, the hormone that regulates lipid and glucose metabolism across tissues. Their dysfunction under lipid stress is central to type 2 diabetes. Organoid and chip systems provide ways to study this process with high temporal resolution. Dishinger et al. created a microfluidic chip to continuously measure insulin secretion from single islets, demonstrating that free fatty acid exposure abolished pulsatile insulin release, a key marker of β-cell dysfunction(9). Bandak et al. similarly showed that while saturated fatty acids impair insulin oscillations, beneficial lipid species such as FAHFAs improve insulin secretion patterns in microfluidic assays(10). These findings underscore how organ-on-chip technologies reveal the direct influence of lipid stress on pancreatic function.
Skeletal muscle
Skeletal muscle consumes large amounts of fatty acids during activity and is crucial for maintaining insulin sensitivity. Muscle-on-chip systems reproduce human myofiber alignment, contractility, and metabolism under controlled environments. Kim et al. reported a skeletal muscle-on-chip that, when tested in microgravity, showed a metabolic shift toward fatty acid use but impaired regeneration capacity. Treatment with candidate drugs partially restored muscle function, highlighting the platform’s potential to screen interventions for lipid-related muscle dysfunction(11).
Intestine
The intestine is the site of dietary lipid absorption and chylomicron production, critical for delivering fats to adipose tissue and liver. Intestine-on-chip models recreate villus-like structures, barrier function, and flow conditions. Bein et al. used an intestine-on-a-chip with patient-derived cells to model environmental enteric dysfunction, showing that nutrient deficiency caused villus atrophy, barrier breakdown, and impaired fatty acid uptake, closely resembling clinical pathology(12). This demonstrates how gut-on-chip platforms can shed light on how dietary and environmental factors shape lipid handling.
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A Multi-Organ Perspective: How Organ-on-Chip Systems Reveal Disease Mechanisms
Metabolic diseases like non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are systemic conditions, not isolated organ failures. They arise from complex and dysfunctional communication between multiple tissues. Traditional in vitro 2D cell cultures and even animal models often fail to capture this intricate inter-organ dialogue, limiting our understanding and the development of effective therapies. To truly decipher these diseases, we must study organ crosstalk. Advanced organoids for metabolic disease research is meeting this challenge by using microfluidic organ-on-chip platforms. These systems connect different tissues, such as liver organoids and adipose tissue organoids, in a single, dynamic device, allowing scientists to observe how these tissues communicate in real-time and providing insights that are impossible to obtain from studying organs in isolation.
The Gut-Adipose-Liver Axis
The dialogue between fat, the gut, and the liver is central to NAFLD. In one pivotal study, an adipose-liver human-on-a-chip model was essential to demonstrate how inflammation drives liver steatosis. Researchers found that when adipose tissue was included, the inflammatory signal TNF-α induced significant fat accumulation (steatosis) in the liver cells—an effect that was completely absent when liver cells were cultured alone. The platform enabled the monitoring of altered adipokine secretion, such as adiponectin, revealing how dysfunctional adipose tissue directly impacts liver health(15). Similarly, an integrated gut-liver-on-a-chip platform revealed a protective crosstalk; co-cultured gut and liver cells were shielded from apoptosis when treated with high levels of free fatty acids, a protective effect not observed in monocultures. This underscores that signals from surrounding metabolic organs are required to initiate and modulate key features of liver disease(16).
Pancreatic Crosstalk with Liver and Muscle
The interplay between the pancreas and other organs is crucial for glucose control. An organ-on-chip system that functionally coupled liver organoids (spheroids) and pancreatic islets was necessary to reconstruct a physiological feedback loop. Insulin secreted from the islets in response to glucose stimulated uptake by the liver, which in turn lowered glucose levels and modulated subsequent insulin secretion—a dynamic, self-regulating system that cannot be replicated in single-organ cultures(17).
Another study using a connected liver-pancreas system demonstrated that a liver model mimicking early metabolic syndrome could induce pancreatic islet dysfunction only when the two systems were coupled. The standalone pancreatic model showed no significant dysfunction under the same media conditions, proving that specific hepatokines (like Fetuin A) secreted by the diseased liver were directly responsible for impairing the pancreas(18).
Beyond the liver, muscle tissue also communicates with the pancreas. A “Training-on-a-Chip” featuring functional, contracting 3D muscle tissue was required to show that electrical stimulation mimicking exercise causes the release of myokines (like IL-6) that directly trigger insulin secretion from pancreatic cells. This provided direct evidence for the beneficial exercise-pancreas link, an interaction that could only be confirmed by studying the two organs in communication(19).
Modeling Systemic Disease and Complications
Systemic diseases like T2D involve even more complex crosstalk. A triple organ-on-chip model incorporating the pancreas, liver, and adipose tissue organoids was necessary to fully recapitulate the key pathological features of T2D and its complications. Using 3D printing with tissue-specific bioinks, this platform showed that disease characteristics only appeared when all three organs could interact within a hyperglycemic environment. This model was so accurate that it could predict the clinical efficacy of T2D medications(20).
This multi-organ crosstalk also extends to other diseases, such as cancer. For instance, co-culture models using a 3D fibrin matrix were essential to keep primary adipocytes viable to show that adipose tissue organoids from obese individuals amplify the transfer of fatty acids to breast cancer cells, potentially fueling tumor progression(21). Other work has shown that factors from both lean and obese adipose tissue can induce a partial mesenchymal-to-epithelial transition in cancer cells, giving them hybrid properties associated with more aggressive tumors(22).
These examples powerfully illustrate that microfluidic organ-on-chip systems are a necessity for modern metabolic research. By connecting different organoids, these platforms allow us to decipher the intricate conversations between organs that drive health and disease. It is this essential crosstalk, revealed by technologies like liver organoids and adipose tissue organoids on a chip, that holds the key to developing personalized therapies and ultimately conquering complex metabolic diseases.
Conclusion & Future Directions
In summary, organoids for lipid metabolism and organ-on-chip models offer transformative platforms to explore how key organs like the liver, adipose tissue, pancreas, muscle, and intestine manage fats in health and disease. These technologies enable precise modeling of lipid uptake, hormonal interplay, and metabolic dysfunctions underlying obesity, NAFLD, and diabetes.
Looking ahead, the next leap forward lies in multi‐tissue integration, combining vascularized, immune-enabled, and perfused organoids on-chip, to better mimic systemic lipid trafficking and inter-organ crosstalk. Such advances promise to accelerate metabolic disease modeling and drug discovery, bridging human physiology and predictive preclinical testing.
References
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