Nutrient excess stimulates β-cell neogenesis in zebrafish.

Area of Science:

• Endocrinology
• Developmental Biology
• Comparative Physiology

Background:

• Mammalian beta-cell (insulin-producing cell) expansion compensates for nutrient excess.
• The adaptive capacity of beta-cells in nonmammalian vertebrates remains largely unexplored.
• Zebrafish serve as a valuable model for studying genetic and chemical genetics in vertebrates.

Purpose of the Study:

• To investigate whether zebrafish beta-cells increase in number in response to nutrient excess.
• To elucidate the underlying mechanisms of beta-cell proliferation or differentiation.
• To determine if nutrient-specific pathways regulate beta-cell adaptation in zebrafish.

Main Methods:

• Culturing transgenic zebrafish larvae in nutrient-altered solutions (glucose, lipid-rich diet).
• Utilizing lineage tracing and marker expression analyses to track beta-cell origins.
• Employing genetic manipulations targeting mammalian target of rapamycin (mTOR) and insulin/IGF-1 signaling pathways.

Main Results:

• Persistent exposure to glucose or a lipid-rich diet significantly increased zebrafish beta-cell numbers.
• The glucose-induced response required mammalian target of rapamycin (mTOR) activity, while the lipid-rich diet response did not.
• Inhibition of insulin/IGF-1 signaling blocked the lipid-rich diet response but not the glucose response.
• New beta-cells originated from the differentiation of postmitotic precursor cells, identified by nkx2.2 and mnx1 promoter activity, not beta-cell self-replication.

Conclusions:

• Nutrient excess triggers a rapid increase in zebrafish beta-cells via differentiation of distinct precursor subpopulations.
• The mechanisms mediating beta-cell adaptation differ based on nutrient type (glucose vs. lipids).
• Paracrine signaling between differentiated beta-cells and precursors likely plays a role in this adaptive process.