Obesity and the Pancreas: From Inflammation to Cancer—and Can Weight Loss Reverse the Trajectory

A new review in Nutrients brings together what is often considered in isolation: how excess body fat — especially visceral fat and fat within the pancreas itself — increases the risk of acute and chronic pancreatitis and accelerates the path to pancreatic cancer. The authors covered the mechanics of the process — from lipotoxicity and immune imbalance to adipokines and insulin resistance — and added a practical layer: what weight loss, incretin-based drugs (GLP-1, dual GIP/GLP-1 agonists), endoscopic techniques, and bariatric surgery do for the prevention and course of “pancreatic” diseases. The conclusion is short: obesity is a multi-path risk factor for the pancreas, and proper weight loss can shift the trajectory of the disease in a safer direction.

Background

Obesity has become one of the main “drivers” of pancreatic diseases in recent decades. It’s not just about the number on the scale: visceral fat and ectopic fat deposits in the pancreas itself (intrapancreatic fat, IPF) are especially dangerous. Such fatty infiltration changes local biochemistry, increases inflammation, and makes tissue vulnerable to both acute damage (pancreatitis) and long-term oncogenic shifts.

• Obesity increases the risk of acute pancreatitis (AP) and makes its course more severe: more necrosis, organ failure and complications.
• In chronic pancreatitis (CP), metabolic disturbances, IPF and insulin resistance accelerate fibrosis and impair exocrine/endocrine function.
• For pancreatic cancer, obesity is an independent risk factor for earlier onset: chronic inflammation, adipokines and insulin signals create the “soil” for the tumor.

In acute scenarios, hypertriglyceridemia and cholelithiasis, which are more common with excess weight, play a key role. During an attack, pancreatic lipase breaks down triglycerides in the inflammation focus, releasing non-esterified fatty acids - they are toxic to acinar cells, disrupt mitochondria and calcium homeostasis, spinning up necrosis and a systemic inflammatory response. Additional fuel is fatty "inclusions" inside the gland itself (IPF): they are available for local lipolysis and support the fire of inflammation.

• Factors through which obesity "fuels" pancreatic damage:

1. Lipotoxicity (fatty acids, ceramides) → cellular stress and necrosis.
2. Systemic inflammation (IL-6, TNF-α) and NF-κB activation.
3. Insulin resistance/T2DM → hyperinsulinemia, IGF signals.
4. Adipokines (↑leptin, ↓adiponectin) with pro-fibrotic/proliferative effect.
5. Changes in microbiota and its metabolites affecting the immune environment.

In pancreatic oncology, the same ligament works “at a long distance”. Dysfunctional adipose tissue behaves like an endocrine organ: chronic inflammation, PI3K/AKT/mTOR and JAK/STAT signals, stromal remodeling worsen tumor sensitivity to chemotherapy. Epidemiologically, high BMI and weight gain are associated with higher risk and worse survival.

Weight loss is logically considered a multi-channel preventive and therapeutic strategy for the pancreas: it reduces visceral and intraorgan fat, improves insulin sensitivity, and reduces the degree of systemic inflammation. The tools - from lifestyle to pharmacotherapy, endoscopic techniques, and bariatric surgery - vary in power and risks, but the goal is the same: to “cool” the inflammatory background and remove metabolic pressure on the gland.

• Practical emphases that form the context of the review:
  • GLP-1 agonists and dual GIP/GLP-1 agonists (tirzepatide) provide significant weight loss and metabolic benefits; large RCTs and meta-analyses do not confirm an increased risk of clinically significant AP/pancreatic cancer, although caution and monitoring remain.
  • Endoscopic solutions (balloons, duodenal liners) are metabolically effective; cases of pancreatitis have been described with some devices - selection and observation are important.
  • Bariatric surgery is the most powerful and sustainable method with a long-term reduction in cancer risk; a surge in gallstone disease is possible in the first months → prophylaxis with ursodeoxycholic acid makes sense.
  • In CP, nutrient deficiencies and osteopenia/osteoporosis are common: along with weight loss, competent nutritional support and PZE (enzymes) are needed.

Technologically, the field is rapidly advancing in non-invasive assessment of pancreatic fat and fibrosis (MRI protocols, PDFF, multicenter standards), and genetic and Mendelian analyses increasingly point to the causal role of pancreatic fat. But the main practical conclusion is already clear: obesity "hits" the pancreas from several fronts at once, and therefore any valid strategies for sustainable weight loss are not cosmetics, but prevention of pancreatitis and potentially cancer risks.

What's new and important in this review

• Obesity increases the risk and aggravates the course of acute pancreatitis (AP) - not only through "classic" gallstones and hypertriglyceridemia, but also due to intrapancreatic fat, which serves as fuel for inflammation. The tendency to severe forms, complications and organ failure is higher with high BMI and waist circumference.
• In chronic pancreatitis (CP), the role of obesity is ambiguous: pancreatic fat and metabolic failures are associated with progression, but in some observations, an “obesity paradox” is also encountered (background fibrosis was sometimes associated with less severe episodes of “acute-on-chronic”). Careful, cause-and-effect studies are needed.
• For pancreatic cancer (PC), obesity is an accelerator of carcinogenesis: chronic inflammation, adipokine imbalance, NF-κB and PI3K/AKT/mTOR axes, and probably microbiota form the “soil” for the tumor; in those already ill, excess weight often worsens the prognosis.
• Weight loss works in multiple ways. Reducing visceral and organ fat, improving insulin sensitivity, and reducing systemic inflammation are the common currency of pancreatic benefit; the range of tools ranges from lifestyle to pharmaco-, endoscopic, and surgical interventions.

How Obesity 'Paves the Way' to Pancreatitis

• Stones and bile. Obesity increases the lithogenicity of bile and hypomotility of the bladder - the risk of biliary OP increases.
• Hypertriglyceridemia. During an attack, lipase breaks down TG with the release of non-esterified fatty acids - they damage acinar cells, disrupt mitochondria and calcium homeostasis, and increase necrosis.
• Insulin resistance and T2DM. Oxidative stress and proinflammatory cascades add fuel to the fire; some therapies have long been suspected of being associated with OP (see below), but large RCTs have not confirmed the concerns.
• Intrapancreatic fat (IPF). Fatty "inclusions" inside the gland - a ready substrate for lipolysis and local inflammation, are associated with both the risk and severity of AP.

The picture is more complex with CP. On the one hand, obesity and “fatty pancreas” are associated with fibrosis and metabolic disorders; on the other hand, there are data where pronounced fibrosis “protects” from the most severe flare-ups of acute inflammation against the background of CP. At the same time, patients with CP typically have deficiencies of fat-soluble vitamins and decreased bone mass - nutritional support remains the cornerstone of management. The review also notes progress in MRI metrics for non-invasive assessment of fibrosis (for example, multicenter protocols such as MINIMAP) and even genetic/Mendelian clues in favor of the causal role of fat in the gland.

Obesity and Pancreatic Cancer: Mechanisms and Facts

• Epidemiology. Meta-analyses and consortia (PanScan, etc.) consistently show that the higher the BMI, the higher the risk of MS; weight gain is associated with earlier onset and worse survival.
• Biology. Dysfunctional adipose tissue functions as an endocrine organ: proinflammatory cytokines, leptin/adiponectin, insulin/IGF signals activate tumor pathways and remodel the stromal “shell”, worsening the response to chemotherapy.
• Microbiota. Evidence is growing on the role of intestinal flora in pancreatic carcinogenesis - from metabolites to immune "tuners".

What does weight loss give - tools and their "pancreatic profile"

• Incretins (GLP-1 agonists).
  • Significantly reduce body weight, improve glycemic control and cardiac risk.
  • Fears of OP/cancer have not been confirmed in large RCTs and meta-analyses (LEADER, SUSTAIN-6, etc.); regulators (EMA/FDA) do not see a proven cause-and-effect relationship.
  • In cancer models, there are hints of antiproliferative effects (inhibition of NF-κB, PI3K/AKT/mTOR, increased chemosensitivity), but this has not been proven in the clinic.
  • Contraindications in people with MEN2/familial medullary thyroid cancer remain.
• Dual GIP/GLP-1 agonists (tirzepatide).
  • Record weight loss in the SURMOUNT/SURPASS programs.
  • According to the summary data of RCTs - no increase in the risk of clinically confirmed OP; favorable dynamics of insulin resistance and hormones, potentially important for "pancreatic" biology.
  • Long-term observation continues.
• Endoscopic methods.
  • Gastric balloons (IGB) - an option for those who are not indicated/do not need surgery: provide short-/medium-term weight loss and metabolic gain.
  • Duodenojejunal liner (DJBL) is metabolically effective, but cases of pancreatitis have been described (device migration, compression of the ampulla area). Vigilance is needed.
• Bariatric/metabolic surgery.
  • The most powerful and sustainable tool for weight loss with systemic benefits.
  • In the first years after surgery, the risks of stone formation and pancreatitis slightly increase against the background of rapid weight loss - prevention with ursodeoxycholic acid helps.
  • Observational data and meta-analyses indicate a reduced risk of cancer, including pancreatic cancer, in patients who have undergone surgery.

Bottom line: excess body weight affects the pancreas “from several fronts at once” - mechanically (stones, blood viscosity in hypertriglyceridemia), metabolically (insulin resistance, lipotoxicity, IPF) and immune/endocrinely (cytokines, adipokines). Therefore, any strategies that remove visceral and intraorgan fat and suppress inflammation potentially shift outcomes - from a lower probability of severe AP to a more favorable oncoprognosis.

What does this mean for the clinic and the individual?

• Risk factor screening. In patients with obesity and/or T2DM, it is worthwhile to actively search for and eliminate “pancreatic” triggers: gallstone disease, high triglycerides, alcohol, drugs with known risk signals.
• Weight loss as a therapeutic goal. A realistic ladder: lifestyle → incretins/dual agonists → endoscopic solutions → surgery. Choice based on risk, comorbidity and motivation.
• After bariatrics - stone prevention. Losing weight quickly - discuss UDCA and gallbladder/symptom monitoring.
• No false alarm about GLP-1. To date, large RCTs do not confirm an increased risk of pancreatitis/pancreatic cancer with GLP-1; benefits (weight, glycemia, CV events) are confirmed. The decision is always personalized.

Restrictions

This is a narrative review: there is no quantitative meta-analysis and no formal risk of bias assessment; some conclusions are based on associations and mechanistic data. Policy and clinical practice need RCTs/registries that directly test whether a given weight loss modifies the risk of first episode of AP, changes the trajectory of CP, and reduces long-term risk of pancreatic cancer.

Source: Souto M., Cúrdia Gonçalves T., Cotter J. Obesity and Pancreatic Diseases: From Inflammation to Oncogenesis and the Impact of Weight Loss Interventions. Nutrients, July 14, 2025; 17(14):2310. Open access. https://doi.org/10.3390/nu17142310