Keywords: Transient receptor potential, Dietary modulators, Gut hormones, Insulin, Obesity
Introduction
Obesity has become a primary health concern during the 21st century. Due to its increasing prevalence since 1970 in several countries, obesity has been declared as a global pandemic(Blüher, 2019; Friedrich, 2017). It has been estimated that about 1.9 billion adults were overweight and 600 million were obese in 2013(Ng et al., 2014) and these numbers would increase significantly by 2030 affecting nearly 51% of the population worldwide (Finkelstein et al., 2012). Obesity is a multifactorial, chronic disease characterized by the excessive accumulation of fat which not only affects the quality of life but also leads to the development of many other metabolic complications(Manna & Jain, 2015). Obesity has been reported to be linked with insulin resistance, type II diabetes, cardiovascular diseases, dyslipidemia, kidney diseases and even cancer(Abdelaal, le Roux et al., 2017). The most pernicious outcome of the obesity is type 2 diabetes. Due to a strong correlation between obesity and the risk for developing type 2 diabetes, the twin epidemic of diabesity has become a global crisis. The global economic burden associated with the obesity is very high, with an estimated cost of US $2.0 trillion or 2.8% of the global gross domestic product (GDP)(Tremmel, Gerdtham et al., 2017). At the same time, diabetes has grown very rapidly in both developed and low-income developing countries. It has been reported that in 2019, 463 million people were diabetic worldwide, and if actions were not taken to prevent the disease, this number would reach 578 million by 2030 and 700 million by 2045(Saeedi et al., 2019). The health care burden associated with diabetes is too high, with an estimated global health expenditure of USD 760 billion in 2019 and is estimated to reach USD 825 billion by 2030 and USD 845 billion by 2045(Williams et al., 2020).
Imbalance in the energy intake and energy expenditure has been linked to the development of obesity, that further leads to the progression of insulin resistance. In this context, targeting gut hormones controlling total dietary intake, adaptive thermogenesis and enhancement of energy expenditure are of great importance to deal with the progress of the disease(Church & Martin, 2018; Rodgers, Tschöp et al., 2012). Lifestyle modifications including diet management and physical activity, are salient factors to manage and prevent diabesity. The most common treatments for diabesity are pharmacological interventions, including drugs targeting insulin secretion from the pancreas, or incretins which improves glucose homeostasis and administration of insulin(Pappachan, Fernandez et al., 2019). Despite available treatments and interventions, there is a continuous race for the development of new therapeutics for diabesity.
Transient receptor potential (TRP) channels superfamily is comprised of a large group of cation permeable channels(C. L. Huang, 2004). Till date, there are 30 known channels of this superfamily and based on their sequence homology, these channels have been divided into 7 families i.e., TRPV (V anilloid), TRPC (C anonical), TRPM (M elastatin), TRPA (A nkyrin), TRPP (P olycystin), TRPML (M ucolipin) and TRPN (N OMP-C)(Nilius & Flockerzi, 2014; J. L. Wu, Sweet, & Clapham, 2010). TRP channels which are expressed in neuronal and non-neuronal tissues, have different physiological functions such as sensory (vision, hearing, taste perception, nociception olfaction, thermo-sensation, and mechano-sensation), cell survival, growth and homeostasis (absorption and reabsorption of ions and fluid flow)[See review(Nilius & Owsianik, 2011)]. Recent evidences from the in-vitro as well asin-vivo studies revealed the presence of these channels in different organs including adipocytes, hypothalamus, liver, pancreas and intestine and their potential role in maintaining energy homeostasis [See review (Bishnoi, Khare, & Brown, 2018)].
TRPA1 which owes its name due to the presence of long 14 ankyrin repeats at N-terminal, is a calcium permeable, non-selective cation channel activated by a wide variety of noxious chemical, mechanical and environmental stimuli, pungent compounds present in herbs and plants as well as by many environmental toxins(Zygmunt & Högesättt, 2014). The important cellular factors responsible for modulating the TRPA1 channel activity include intracellular calcium ion concentration(Zurborg, Yurgionas et al., 2007), pH(Fumitaka Fujita et al., 2008), reactive oxygen(Arenas et al., 2017), nitrogen and carbonyl species[ for more details refer to review by (Talavera et al., 2020)]. TRPA1 is largely known for its role in pain, neurogenic inflammation, itchetc .,(Xiao & Patapoutian, 2011) but continuous growing evidence from many experiments suggested the importance of TRPA1 channel in other physiological functions including gastric motility, insulin secretion and in the prevention of weight gain(Kagawa, Ozaki‑Masuzawa et al., 2019; Khare et al., 2016; M. J. Kim et al., 2013). The present review focuses on TRPA1 structure, its physiological importance, channel modulation by agonists and antagonists, its role and possible mechanisms in prevention and therapeutics of obesity and related complications.