Regulation of metabolic homeostasis by the TGF‐β superfamily receptor ALK7

Abstract

superfamily predominantly expressed by cells and tissues involved in endocrine functions, such as neurons of the hypothalamus and pituitary, pancreatic bcells and adipocytes. Recent studies have begun to delineate the processes regulated by ALK7 in these tissues and how these become integrated with the homeostatic regulation of mammalian metabolism. The picture emerging indicates that ALK7's primary function in metabolic regulation is to limit catabolic activities and preserve energy. Aside of the hypothalamic arcuate nucleus, the function of ALK7 elsewhere in the brain, particularly in the cerebellum, where it is abundantly expressed, remains to be elucidated. Although our understanding of the basic molecular events underlying ALK7 signaling has benefited from the vast knowledge available on TGF-b receptor mechanisms, how these connect to the physiological functions regulated by ALK7 in different cell types is still incompletely understood. Findings of missense and nonsense variants in the Acvr1c gene, encoding ALK7, of some mouse strains and human subjects indicate a tolerance to ALK7 loss of function. Recent discoveries suggest that specific inhibitors of ALK7 may have therapeutic applications in obesity and metabolic syndrome without overt adverse effects.

The orphan ligand, activin C, signals through activin receptor-like kinase 7

“…Furthermore, gene expression of both Pparg2 and Cebpa, essential transcription factors for adipogenesis, was impaired by ActA or ActB but not ActC ( Figure 6G ). However, ActC significantly reduced both Pnpla2 expression and lipid content, consistent with the late-stage, proadipogenic effects of ActB-ALK7 signaling ( Figure 6G ; Ibáñez, 2021 ; Hoggard et al, 2009 ; Hirai et al, 2005 ; Nielsen, 2009 ).…”

“…ActB has dual effects on adipogenesis, and its function depends on the relative expression of ALK4 and ALK7 during the process of adipocyte commitment and differentiation ( Carlsson et al, 2009 ; Guo et al, 2014 ; Ibáñez, 2021 ; Kogame et al, 2006 ). ActA or ActB exposure during differentiation of SVF cells, when ALK7 levels are low, inhibits adipogenesis ( Figure 6F ).…”

The orphan ligand, Activin C, signals through activin receptor-like kinase 7

“…However, ActC significantly reduced both Pnpla2 expression and lipid content, consistent with the late-stage, proadipogenic effects of ActB-ALK7 signaling (Fig. 6G) 43,[45][46][47] .…”

“…However, given the ability of the ligands to signal via ALK7, we turned our attention to adipocytes. Human adipose tissue is a major site of both ActB and ALK7 expression, where the pair induces proobesity signaling outcomes, such as catecholamine resistance or inhibition of lipolysis 29,43,51 . In this study, we show that ActC regulates adipocyte differentiation differently than ActA or ActB.…”

“…ActB has dual effects on adipogenesis, and its function depends on the relative expression of ALK4 and ALK7 during the process of adipocyte commitment and differentiation 24,29,43,44 . ActA or ActB exposure during differentiation of SVF cells, when ALK7 levels are low, inhibits adipogenesis (Fig.…”