The study's central question is to determine the role of peripancreatic adipose tissue (PAT), a relatively understudied visceral fat depot, in the development of metabolic disturbances associated with obesity. The prevailing view contrasts subcutaneous adipose tissue, often considered "good fat" due to its protective effect against ectopic lipid deposition, with visceral adipose tissue, deemed "bad fat" due to its association with metabolic syndrome and insulin resistance. However, visceral adipose tissue is heterogeneous, and regional differences in lipolysis, fatty acid storage, adipokine secretion, and gene expression exist. Intrapancreatic adipocytes, located within the pancreas, have been linked to diabetes development, but their functional relationship with PAT remains unclear. PAT, distinct from intrapancreatic adipocytes, contains both adipocytes and non-adipocytes and has been implicated in obesity-induced beta-cell proliferation and pancreatic neoplasia. The study aims to elucidate PAT's intrinsic characteristics and its potential role in diabetes development by comparing its morphology and function to other adipose tissue depots (mesenteric, gonadal, and inguinal) in mice.

Existing research highlights the association between visceral adiposity and increased risk of metabolic diseases like diabetes and insulin resistance. Studies have shown that increasing subcutaneous adipose tissue capacity protects against ectopic lipid deposition, while excessive visceral fat accumulation is linked to metabolic complications. Partial lipectomy of visceral fat has demonstrated metabolic improvements, further supporting this concept. However, visceral fat depots display regional differences in their metabolic and immunological profiles, prompting the need for further investigation into specific visceral fat depots beyond the broadly defined visceral category. Previous studies have focused on intrapancreatic adipocytes, showing their involvement in diabetes. Limited research has been conducted on PAT, but some studies suggest a potential role in beta-cell proliferation and inflammation, leading to the hypothesis of a potential role in metabolic regulation and disease progression.

Male C57BL/6J mice were fed either a standard chow diet or a high-fat diet (HFD) for varying durations (1, 4, 8, and 16 weeks). Four adipose tissue depots (inguinal, mesenteric, gonadal, and peripancreatic) were collected and analyzed for adipocyte size, cellular composition (using flow cytometry), lipogenesis, lipolysis, and gene expression. In vivo lipid and glucose metabolism were assessed using radioactive tracers. In a separate experiment, PAT was surgically removed from mice before HFD feeding, and the effects on glucose tolerance, insulin levels, hepatic and pancreatic steatosis, and gene expression were evaluated. Statistical analysis was conducted using one-way or two-way ANOVA, two-tailed Student's t-test, and Pearson correlation.

PAT, a small fat depot (approximately 0.2% of total fat mass), contained smaller adipocytes and a high proportion of stromal vascular cells (leukocytes and fibroblasts) compared to other fat depots. PAT exhibited higher glucose uptake and fatty acid oxidation in both lean and obese mice. Importantly, PAT weight correlated positively with liver weight in obese mice (R=0.65; p=0.009). Surgical removal of PAT exacerbated hepatic steatosis (p=0.008) and elevated basal (p<0.05) and glucose-stimulated insulin levels (p<0.01) in HFD-fed mice. PAT removal also resulted in enlarged pancreatic islets and increased expression of markers associated with glucose-stimulated insulin secretion and islet development (p<0.05). Gene expression analysis revealed differences in the expression of genes related to lipogenesis, inflammation and mitochondrial function between PAT and other fat depots. PAT showed less responsiveness to HFD-induced changes in gene expression related to adiponectin, TNFα, F4/80 and MCP1 compared to other fat depots. These findings suggest a distinct metabolic role for PAT.

The findings demonstrate that PAT, despite its small size, plays a previously unrecognized role in regulating metabolic homeostasis in the context of obesity-induced insulin resistance and hepatic steatosis. The positive correlation between PAT weight and liver weight in obese mice, along with the detrimental effects of PAT removal on metabolic parameters, suggests a protective function of PAT against ectopic lipid accumulation in the liver. The unique cellular composition of PAT, with a higher proportion of stromal vascular cells, may contribute to its metabolic activity. Furthermore, the differential gene expression profile of PAT compared to other fat depots indicates its distinct metabolic regulation. These results challenge the simplistic "good fat" versus "bad fat" dichotomy and highlight the importance of considering regional differences within the visceral adipose tissue compartment. Future studies could investigate the specific cellular and molecular mechanisms by which PAT exerts its metabolic effects and explore potential therapeutic strategies that target PAT to improve metabolic health in obesity.

This study demonstrates that PAT is a small but metabolically active fat depot that plays a previously unknown protective role against the development of hepatic steatosis and insulin resistance in obesity. Surgical removal of PAT worsened metabolic parameters in mice fed a high-fat diet. These findings suggest that PAT may be a potential therapeutic target for treating metabolic disorders associated with obesity. Future research should focus on identifying the specific mechanisms by which PAT exerts these effects and exploring potential therapeutic interventions targeting PAT.

The study was conducted using only male C57BL/6J mice, limiting the generalizability of the findings to other strains and sexes. The surgical removal of PAT may have caused unintended effects that confounded the results, although a sham surgery was performed for comparison. Further studies are needed to fully elucidate the cellular and molecular mechanisms underlying the metabolic effects of PAT.