Research

#1Regulation of host homeostasis via gut microbial metabolites and short-chain fatty acids receptors
#2Sex differences-related disorders via sex steroid hormone and the receptors
#3Molecular nutritional signaling via free fatty acids receptors

Our research aims at understanding the molecular mechanism of homeostasis maintaining, especially focuses on dietary/nutritional function, endocrine metabolism, and cancer. Based on this research, we aim to provide valuable insight into the development of functional foods, supplements, and medicinal drugs.

Regulation of host homeostasis via gut microbial metabolites and short-chain fatty acids receptors

This research aims at elucidating the molecular interplay between host energy metabolism and the multitude of metabolites of gut microbiota that underlies the pathogenesis of metabolic disorders with further exploration of novel interventions including drugs and functional foods.

Metabolic disorders, such as obesity and diabetes, arise from disrupted energy homeostasis that depends upon the equilibrium between energy intake and expenditure. Gut microbiota has emerged as a pivotal, multifactorial mediator in these disorders as it remarkably regulates host energy acquisition and metabolism while being modified by diet. Short-chain fatty acids (SCFAs), which primarily include acetate, butyrate, and propionate, represent an essential subset of gut microbial metabolites derived from the fermentation of the otherwise indigestible dietary fiber. We previously reported that SCFAs play an important role in the regulation of energy homeostasis via specific receptors (e.g., GPR41 and GPR43) that are present in host tissues. Specifically, GPR41 mediates sympathetic activity and GPR43 is primarily involved in the adipose-insulin signaling (Kimura et al. Science. 2020, Kimura et al. Nat Commun. 2013, Kimura et al. PNAS. 2011). Recent evidence suggests that dietary fiber and the gut microbial-derived SCFAs exert multiple beneficial effects on host energy metabolism not only by improving the intestinal environment, but also by directly affecting various host peripheral tissues. The roles of the gut microbiota-derived exopolysaccharides (EPS) in host energy metabolism will also be discussed in detail in order to provide insight into the development of new drugs and functional foods that are effective against the energy-metabolism associated disorders(Miyamoto et al. Gut Microbes. 2023).

Sex differences-related disorders via sex steroid hormone and the receptors

Sex steroid hormones are involved not only in reproductive functions but also in many physiological functions, including maternal behavior, aggression, emotion, feeding, circadian rhythm, sleep, and higher brain functions such as memory and learning. Most of them involve immediate responses that cannot be explained by the nuclear receptors, and the mechanisms are still unclear. Probably, their responses are expected the relationship of membrane sex steroid hormone receptors such as GPR30, MAPRs, mPRs（Kasubuchi et al. Sci Rep. 2017, Ohta et al. Sci Rep. 2015, Kimura et al. J Neurochem. 2010, Kimura et al. JBC. 2008). Recently, we focus on novel membrane progesterone receptors (mPRs), which exhibit fetal and neonatal tissues-specific expression patterns in perinatal period. We aim to investigate the immediate responses of sex steroids and discover the underlying mechanisms, in the view of interindividual multi-sensing biosystems, especially sensing system between mother-child. This research expects to elucidate not only the pathogenesis of perinatal disorders, including developmental disorders, but also the mechanisms of postnatal disease development and novel endocrine mechanisms involving sex difference.

During the perinatal period, fetal growth is influenced by maternal humoral factors, which directly impact the development of various diseases such as allergies, neurological disorders, obesity, and diabetes after birth. Among these factors, we have focused on gut microbial metabolites short-chain fatty acids (SCFAs) and revealed that maternal SCFAs contribute to the development of the nervous and metabolic systems via the fetal SCFAs receptors GPR41 and GPR43, thereby exerting resistance against postnatal obesity (Kimura et al. Science. 2020). In this research, as a further development of elucidating sensing system between mother-child, we focus to sex steroids that rapidly increase in mother during pregnancy. Based on our novel finding that the mPRs are highly expressed in various sensory tissues of the fetus during the late stages of pregnancy, we aim to unravel the molecular mechanisms.

Molecular nutritional signaling via free fatty acids receptors

Dietary fatty acids, have been significantly associated with the proneness to obesity and related disorders. Dietary fatty acids are an essential energy source and signaling molecules that regulate various cellular processes and physiological functions. Recently, several orphan G protein-coupled receptors were identified as free fatty acid receptors (FFARs). GPR40 and GPR120 are activated by n-3 or n-6 polyunsaturated fatty acids such as dietary fish and vegetable oil, GPR84 are activated by medium-chain fatty acids including MCT oils, and GPR41 and GPR43 are activated by ketone bodies produced under enery shortage (Kimuera et al. Physiol Rev. 2020). The critical role of dietary metabolites as signaling molecules via theses FFARs has come to be appreciated, the attention has been focused on the relationship between dietary metabolites and regulatyion of homeostasis axis. Our functional analyses have revealed that FFARs are critical for metabolic functions, such as peptide hormone secretion and inflammation, and contribute to energy regulation（Miyamoto et al. Nat Commun. 2019, Ichimura et al. Nature. 2012, Ohue-Kitano et al. JCI Insight. 2023,Miyamoto et al. PNAS. 2019, Kimura et al. PNAS. 2011).

We believe that research of FFARs will provide valuable insights into therapeutic targets for treating metabolic disorder such as obesity and diabetes.