, 2025-05-02 11:16:00
The understanding of fat has evolved in recent decades. Once regarded as nothing more than passive storage reservoirs for fat, adipocytes are now recognized as critical players in metabolic and endocrine processes. Fat may even be regarded as an endocrine organ, with the metabolic contribution of adipocytes changing as they enlarge in tandem with increasing obesity. Expanding adipose tissue undergoes alterations that not only promote insulin resistance but also produce pro-inflammatory factors.
“It’s become clear from the literature that people with obesity often have a pro-inflammatory state, based on various biomarkers measured in the blood,” Karen Corbin, PhD, RD, associate investigator of Translational Research Institute, AdventHealth, Orlando, Florida, told Medscape Medical News.
Mechanisms linking obesity and inflammation are intricate and far-reaching, according to Alan Saltiel, PhD, professor of medicine and director of the Diabetes Research Center, University of California San Diego. “In recent decades, the quest to find a mechanism connecting the pathogenesis of obesity to insulin resistance and diabetes has shed light on a close relationship between caloric excess and activation of the innate immune system in most organs that play a role in energy homeostasis,” he told Medscape Medical News.
Inflammation may represent a “bridge” linking obesity to its comorbid conditions, such as type 2 diabetes. Understanding inflammation may also illuminate what drives obesity, beyond excess caloric intake.
Chicken vs Egg
The relationship between obesity and inflammation might be seen as a “tough chicken-and-egg question,” said Saltiel. “Obesity definitely causes inflammation; and inflammation, in turn, makes people more susceptible to weight gain through reducing energy expenditure and possibly through mechanisms in the brain that we don’t fully understand, which reduce the brain’s sensitivity to satiety hormones.”
Research supports the role of both the “chicken” and the “egg.” For example, a population-based study found that an array of baseline inflammatory markers (eg, high-sensitivity C-reactive protein [hs-CRP], interleukin-1 receptor antagonist, IL-1Ra, IL-6, tumor necrosis factor–a, and high-molecular-weight adiponectin) were strongly associated with indicators of obesity (elevated weight, body mass index [BMI], waist circumference, and body fat percentage). After adjustment for obesity predictors, hs-CRP and IL-1Ra were inversely associated with changes in obesity indicators during 7-year follow-up. Almost all associations were attenuated after further adjustment for baseline BMI. “These findings suggest that the inflammatory markers, although highly associated with obesity, do not predict weight gain,” the authors concluded. “This could translate into inflammation being a result of obesity, rather than a contributing factor to it.”
On the other hand, inflammation may contribute to fat storage, according to a paper by Jianping Ye and Jeffrey N. Keller. The inflammatory response may induce energy expenditure “in a feedback manner to fight against energy surplus in obesity.” A deficient feedback system (sometimes called inflammation resistance) reduces energy expenditure, leading to energy accumulation, and in turn, contributing to obesity. Caloric restriction may inadvertently contribute to energy saving, which may be one reason it’s so difficult for people with obesity to lose weight and sustain their weight loss.
The Power of Fat Cells
Saltiel’s research focuses on “trying to understand the signaling pathways in cells.” He described fat cells as playing an important part in controlling metabolism, “If you look at pictures of fat cells, at first glance, they look like marshmallows. But they’re much more than simply ‘blobs.’ They’re actually on the cutting edge of sensing the energy in our bodies.” These cells go through a “decision-making process of whether it’s a good time to store or to burn energy.” The cells must be able to sense “how much energy they have on board and send a signal to the other cells in the brain, liver, and tissues, instructing them what to do.”
Fat cells have hormonal receptors that are sensitive to adrenaline, insulin, and other hormones, Saltiel explained. “They’re very plastic, so they enlarge when we feed them and shrink when we fast.” He noted that pictures of fat cells in mice deprived of food for 24 hours, showed cells that are half the size of fat cells in recently fed mice.
However, he continued, there are types of fat cells, some more adaptable than others. “In a normal setting, fat cells shrink when we fast and expand when we feed. When they expand and shrink, they sense that they have more or less energy and release hormones accordingly. Pathways in fat cells sense the breakdown or storage of energy, and then change the expression of genes that encode for these hormones.”
Leptin, discovered in the 1990s, is the most well-known hormone released in response to feeding, he said. “After we eat and the fat cell is full, it releases leptin, which travels to the brain, tells the brain we’re satiated and we should stop eating, and tells the brain to release hormones that increase the breakdown of fat and increase energy expenditure.” Saltiel described this as a “rheostat” or “feedback loop.”
“When we fast, we release fatty acids from fat cells,” Saltiel stated. “They travel to the liver, muscle, brain, and pancreas to instruct those cells to perform a variety of functions, including the release of other hormones.”
In the setting of inflammation, this process can be disrupted. Inflammation dampens the responsiveness of the fat cell to these signals, so they become less plastic and less adaptable. “Adipose tissue responds to overnutrition by mounting an immune response.” The resulting inflammation induces insulin resistance. Additionally, the adipose cells “become more efficient at storing rather than releasing energy, and inflammation may be implicated in suppressing the release of energy and promoting its storage.”
Several questions about this process are subjects of current investigation, Saltiel said. “The first is what triggers the inflammatory response in adipose tissue that occurs in the setting of positive energy balance and drives storage rather than release.” Trying to understand this entails looking at immune cells residing in adipose tissue; what leads to changes in those cells and how those changes take place.
“One hypothesis, which I think is an oversimplification, is that it’s mechanical stress on the fat cell that triggers inflammation,” Saltiel commented. “It’s been suggested that the fat cell expands to accommodate the fat, but it ‘hits a wall’ because there isn’t enough room to expand. That process could trigger inflammation.”
Another hypothesis he cited is that “bacterial products are released into circulation because of the ‘leaky gut’ that occurs during obesity, resulting in inflammation.” Other mechanisms include adipocyte death and hypoxia, which develops due to the expansion of adipose tissue and reduction in oxygen tension. “However,” Saltiel noted, “it’s unclear whether this hypoxia is a consequence of adipose tissue expansion or whether it directly causes obesity-associated metabolic disease.”
Saltiel thinks the answer probably incorporates several hypotheses, together with “other changes in circulating nutrients that make inflammation more likely to happen and prime the fat cell to mount an inflammatory response.”
He noted that inflammation in obesity is “ low-grade and chronic, rather than acute. The long-term effects of inflammation have downstream impact, which is the second major question we’re trying to understand.”
The third question is which particular pathways, triggered by inflammation, change energy balance, promote energy storage, and repress energy use. “A lot of us are working on that question, and there’s controversy surrounding the mechanisms.” Some studies have utilized an anti-inflammatory antibody or small molecule, with “results that are mixed or modest, or show no effect at all.” The problem, Saltiel explained, is that “there’s probably a redundancy of pathways, so we don’t know which specific pathway to target or whether to target a combination of pathways.”
But if the main action of inflammation in obesity is to reduce energy expenditure, then blocking that process by increasing energy expenditure alone is “likely to have a modest effect, at best. This may be why it doesn’t always help to tell people to ‘simply exercise more.’ People get hungrier and compensate by eating more to balance out the energy expenditure.”
Anti-inflammatory therapy could potentially work if combined with therapy that blocks energy intake, such as a glucagon-like peptide 1 receptor agonists (GLP-1 RAs), Saltiel speculated. “But no one has conducted that study yet; and commonly used anti-inflammatory agents like nonsteroidal anti-inflammatory drugs, for example, won’t target inflammation in adipose tissue. It would be interesting to see if other anti-inflammatory drugs coupled with GLP-1 drugs could work together to improve weight loss and metabolic effects.”
Gut Microbiome: Key Player in the Obesity Story
The gut microbiome is garnering increasing attention as a potential connector between inflammation and adipose tissue function. A growing body of research demonstrates that disruption of gut microbiota activates the adaptive and innate immunity in the intestine and raises the inflammatory level.
Corbin has studied the role of gut microbiota in obesity. Her research focuses on the role of gut microbiota in directly contributing to energy balance by “harvesting energy” from undigested components of the diet.
“Of the calories a person eats, most are absorbed in the small intestine,” she explained. “Calories from fiber and resistant starch aren’t digestible, so they end up in the colon. The role of high-fiber diets in preventing illnesses such as colon cancer, or promoting cardiovascular health, is well-known. But what we didn’t know 50 years ago is that, with the right kinds of microbes, nondigestible carbohydrates will be fermented. This is beneficial because fermentation produces primarily short-chain fatty acids, an energy source, and these get reabsorbed by the human being.”
Corbin and her collaborators discovered that the energy produced by the microbes in a healthy colon affects energy balance. They measured energy intake, energy expenditure, and energy output (fecal and urinary) in participants in a metabolic ward, under strictly controlled environmental conditions. Compared with the standard Western diet, the Microbiome Enhancer Diet (MBD) led to an additional 116 ± 56 kcals (P < .0001) lost in feces daily, with no changes in energy expenditure, hunger/satiety or food intake (P > .05).
“When we fed people the MBD, high in fiber and resistant starch and low in processed foods, people lost more calories in excretion and had massive growth and remodeling of the microbes,” summarized Corbin, a spokesperson for The Obesity Society.
These findings may lay the groundwork for potential “precision nutrition,” although several questions still need to be elucidated, said Corbin. Does the gut microbiota play a causal, not merely an associational, role in linking diet and human obesity? What’s the magnitude of its effect size? What’s the impact of caloric restriction or overfeeding on the microbiome? Does inflammation contribute to the dynamics of microbiota involvement? And do individuals with obesity benefit from some version of the MBD, not only in terms of weight loss but also in reducing inflammation?
Diets that include foods associated with lower inflammation might be linked to improvements in microbiome diversity and function. Typically, these include consumption of unrefined and minimally processed foods, nutrients including fiber, mono- and poly-unsaturated fatty acids and lean protein sources, and avoidance of red meat, high-fat dairy foods, saturated and trans fats, and processed foods. The Mediterranean diet, for example, has been shown to reduce inflammatory markers and overweight/obesity, and has improved the population of the gut microbiota. “Given that our MBD had many of the same components as the Mediterranean diet, one could hypothesize that inflammation is a means whereby the microbiome is related to energy balance and adipose function,” Corbin suggested.
“We need a happy, healthy, well-fed microbiome,” she added. “In addition to upgrading one’s diet to include prebiotics and reducing foods associated with inflammation and damage to the microbiota, incorporating some extra physical exercise will also help promote negative energy balance.”
Today’s discoveries may revolutionize our understanding of the mechanisms that drive obesity, including inflammation. Both experts hope that these new insights into inflammatory mechanisms will lead to improved management of obesity and its sequelae.
Saltiel is a founder of Elgia Therapeutics. Corbin disclosed no relevant financial relationships.
Batya Swift Yasgur, MA, LSW is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom(the memoir of two brave Afghan sisters who told her their story).
