Liver-derived Neuregulin1α stimulates compensatory pancreatic β cell hyperplasia in insulin resistance

Takatomo Arai, Eriko Hayashi, Sumie Maeda, Tsutomu Matsubara, Hideki Fujii, Koya Shinohara, Arisu Sogabe, Sadatomo Wainai, Daishi Tanaka, Yutaro Ono, Yumika Ono, Minami Yoshikai, Yuriko Sorimachi, Cindy Yuet-Yin Kok, Masayuki Shimoda, Minoru Tanaka, Norifumi Kawada and Nobuhito Goda ()
Additional contact information
Takatomo Arai: Waseda University
Eriko Hayashi: Waseda University
Sumie Maeda: Waseda University
Tsutomu Matsubara: Osaka Metropolitan University
Hideki Fujii: Osaka Metropolitan University
Koya Shinohara: National Center for Global Health and Medicine
Arisu Sogabe: Waseda University
Sadatomo Wainai: Waseda University
Daishi Tanaka: Waseda University
Yutaro Ono: Waseda University
Yumika Ono: Waseda University
Minami Yoshikai: Waseda University
Yuriko Sorimachi: National Center for Global Health and Medicine
Cindy Yuet-Yin Kok: Neuroscience Research Australia
Masayuki Shimoda: National Center for Global Health and Medicine
Minoru Tanaka: National Center for Global Health and Medicine
Norifumi Kawada: Osaka Metropolitan University
Nobuhito Goda: Waseda University

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Compensatory pancreatic islet hyperplasia is an adaptive response to increased systemic insulin demand, although factors meditating this response remain poorly understood. Here, we show that a liver-derived secreted protein, Neuregulin1α, promotes compensatory proliferation of pancreatic β cells in type 2 diabetes. Liver Neuregulin1α expression and serum Neuregulin1α levels increase in male mice fed an obesity-inducing diet. Male mice lacking either Neuregulin1 in liver or its receptor, ErbB3, in β cells deteriorate systemic glucose disposal due to impaired β cell expansion with reduced insulin secretion when fed the obesity-inducing diet. Mechanistically, Neuregulin1α activates ERBB2/3-ERK signaling to stimulate β cell proliferation without altering glucose-stimulated insulin secretion potential. In patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity but without type 2 diabetes serum Neuregulin1α levels increase, while in patient with MASLD and type 2 diabetes show markedly reduced levels of Neuregulin1α. These results suggest that Neuregulin1α serves as a hepatokine that can expand functional β cell mass in type 2 diabetes.

Date: 2025
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DOI: 10.1038/s41467-025-57167-0

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