Restoring Metabolic Architecture in the South Asian Thin-Outside-Fat-Inside (TOFI) Phenotype: A Mechanistic Rationale for Combining Abscisic Acid and β-Aminoisobutyric Acid.

A large proportion of South Asians exhibit a thin-outside-fat-inside (TOFI) phenotype, also termed metabolically obese normal-weight (MONW); the two terms are used interchangeably in this review. The phenotype combines a normal or near-normal body mass index (BMI) with excess visceral white adipose tissue (WAT), low skeletal muscle mass, low bone mineral density (BMD), and early decline in β-cell function. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), the dominant pharmacological paradigm for obesity and type 2 diabetes (T2D), may be imperfectly matched to this phenotype. They reduce total body weight effectively, but absolute lean mass declines and BMD may fall during treatment. Their obesity indications are also anchored to BMI thresholds that many TOFI patients do not meet, and their use is constrained in frail older adults and in women planning pregnancy. In this narrative review, we examine the pathophysiology of the TOFI phenotype and develop a mechanistic hypothesis for combining two endogenous human metabolites, abscisic acid (ABA) and β-aminoisobutyric acid (BAIBA). The aim of this combination would be to shift the therapeutic target from weight loss toward restoration of body composition and metabolic function. In predominantly preclinical studies, BAIBA, an exercise-induced myokine, promotes uncoupling protein-1 (UCP-1)-dependent browning of WAT through peroxisome proliferator-activated receptor alpha (PPARα). It also supports skeletal muscle through adenosine monophosphate-activated protein kinase (AMPK)-PPARδ signalling and protects osteocytes through Mas-related G protein-coupled receptor member D (MRGPRD). In preclinical and small early human studies, ABA, acting through lanthionine synthetase C-like protein 2 (LANCL2), has been shown to stimulate GLP-1 secretion and to promote insulin-independent, glucose transporter type 4 (GLUT4)-mediated glucose uptake in skeletal muscle. The two molecules appear mechanistically complementary: BAIBA targets fat quality and musculoskeletal preservation, whereas ABA targets glucose disposal independent of β-cell secretory capacity. We propose a conceptual three-pillar model and summarise the evidence for each component according to evidence level. We also review preliminary data from a 12-week, open-label, single-arm, investigator-led cohort of 30 adults with obesity, in which mean body weight fell by approximately 8%, with no serious adverse events, hypoglycaemic episodes or discontinuations reported. No randomised controlled trial of the combination has yet been published. The concept is hypothesis-generating and requires confirmation in randomised controlled trials in South Asian populations, with body-composition, glycaemic and β-cell function endpoints.