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.