What is the clinical evidence from this study?

Study design: Other. Population: Type 2 diabetes with metabolic dysfunction-associated steatotic liver disease (MASLD). Intervention: Insulin resistance and GAN diet vs. Healthy mice and physiological conditions. Primary outcome: De novo lipogenesis and lipid accumulation.

What does this research mean for the field?

During selective hepatic insulin resistance, excess fasting de novo lipogenesis in pericentral hepatocytes—fueled by amino acid catabolism and sustained by the IRS1-mTORC1 signaling axis—drives pericentral steatosis. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to define the mechanisms driving lipogenesis in insulin-resistant hepatic conditions, particularly in T2D.

June 7, 2026

1090-OR: Anatomical Regulation of Glucose and Lipid Metabolism by Insulin Signaling in Hepatocytes

Key Result

Excess fasting de novo lipogenesis in pericentral hepatocytes drives pericentral steatosis during insulin resistance, sustained by hyperinsulinemia via the IRS1-mTORC1 signaling axis.

Key Points

This research aims to define the mechanisms driving lipogenesis in insulin-resistant hepatic conditions, particularly in T2D.
Used Cyp1a2CreER and Gls2CreER for targeted gene deletion in specific hepatocyte regions of adult mice.
Incorporated stable isotope tracing and fluorescence-activated cell sorting to quantify metabolism in periportal and pericentral hepatocytes.
Investigated metabolic differences between healthy and insulin-resistant states in hepatocytes.
De novo lipogenesis is significantly higher in periportal hepatocytes compared to pericentral hepatocytes in healthy mice.
In insulin-resistant conditions, lipid accumulation chiefly occurs in pericentral hepatocytes, revealing a shift in metabolic function.
Fasting DNL in pericentral hepatocytes is maintained by IRS1-mTORC1 signaling, contributing to the progression of steatosis.

Structured PICO

Population

Adult mice and insulin-resistant MASLD patients evaluated for spatial regulation of lipogenesis during insulin resistance.

Exposure

Spatial targeting (deletion of genes specifically in pericentral or periportal hepatocytes) integrated with in vivo stable isotope tracing and fluorescence-activated cell sorting (FACS).

Comparator

Healthy mice (physiological conditions).

Outcome

Zone-specific metabolism, specifically de novo lipogenesis (DNL) and lipid accumulation in periportal vs pericentral hepatocytes.surrogate

Excess fasting de novo lipogenesis in pericentral hepatocytes, driven by the IRS1-mTORC1 signaling axis, promotes steatosis progression during selective hepatic insulin resistance.

Abstract

Introduction and Objective: Type 2 diabetes (T2D) accompanied by metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by unsuppressed hepatic glucose production and elevated de novo lipogenesis (DNL)—a paradoxical combination known as selective hepatic insulin resistance. Accumulating evidence indicates that excessive hepatic DNL is a major contributor to MASLD pathogenesis; however, the mechanisms that drive lipogenesis within the insulin-resistant liver remain poorly defined. Methods: The liver has a repeated lobular organization, in which periportal (PP) hepatocytes and pericentral (PC) hepatocytes exert distinct metabolic functions. Using Cyp1a2CreER, Gls2CreER, and the tdTomato lineage tracer, we delete genes specifically in PC or PP hepatocytes of adult mice and permanently mark these deleted cells. We integrate this spatial targeting with in vivo stable isotope tracing and fluorescence-activated cell sorting (FACS) of hepatocytes to quantify zone-specific metabolism. Results: We found that DNL is higher in PP hepatocytes than in PC hepatocytes in healthy mice. In contrast, insulin-resistant MASLD patients and diet-induced obese mice consistently exhibit lipid accumulation predominantly in PC hepatocytes—a phenomenon termed pericentral steatosis. These observations suggest that spatial regulation of lipogenesis during insulin resistance differs fundamentally from physiological conditions. Here, we show that during insulin resistance, excess fasting DNL in PC hepatocytes drives pericentral steatosis in mice fed a GAN diet. Mechanistically, amino acid catabolism supplies carbon substrates for lipogenesis, while fasting hyperinsulinemia sustains activation of lipogenic gene expression through the IRS1-mTORC1 signaling axis specifically in PC hepatocytes. Conclusion: Together, these spatially coordinated metabolic and signaling mechanisms promote steatosis progression during selective hepatic insulin resistance in T2D. Disclosure R. Tao: None. Funding R01DK133388

Bookmark

Cite This Study

Rongya Tao (Fri,) conducted a other in Type 2 diabetes with metabolic dysfunction-associated steatotic liver disease (MASLD). Insulin resistance and GAN diet vs. Healthy mice and physiological conditions was evaluated on De novo lipogenesis and lipid accumulation. Excess fasting de novo lipogenesis in pericentral hepatocytes drives pericentral steatosis during insulin resistance, sustained by hyperinsulinemia via the IRS1-mTORC1 signaling axis.

synapsesocial.com/papers/6a250c957def13d035e1cc22 https://doi.org/https://doi.org/10.2337/db26-1090-or

Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

Bookmark