Impact of Asprosin and Neuregulin 4 on Metabolic Parameters, Anthropometric Indices and Body Composition After Laparoscopic Sleeve Gastrectomy

The Impact of Asprosin and Neuregulin 4 on Metabolic Parameters, Anthropometric Indices and Body Composition After Laparoscopic Sleeve Gastrectomy: Protocol for a Prospective Longitudinal Cohort Study With a Non-obese Reference Group and a Nested Mixed-meal Sub-study (ASPEN-SG)

Asprosin and neuregulin 4 (NRG4) sit on opposing arms of adipose endocrine physiology. Asprosin is a fasting-induced, white adipose-derived glucogenic and orexigenic hormone that rises with adiposity and insulin resistance. NRG4 is a brown and beige adipose-derived, anti-lipogenic and hepatoprotective factor that falls with adiposity. Both have been examined separately after metabolic and bariatric surgery, but never in the same cohort, and existing surgical data cannot separate a weight-loss-dependent effect from an effect of the operation itself.

Objectives: To quantify the change in fasting serum asprosin and NRG4 over twelve months after laparoscopic sleeve gastrectomy (LSG); to determine whether those changes are associated with metabolic improvement independently of weight loss; and to characterise their relationship with anthropometric indices and body composition.

Adipose tissue is an endocrine organ whose secretory profile changes profoundly after metabolic and bariatric surgery. Two of its products have attracted attention for opposite reasons, and the relationship between them has never been examined in a surgical population.

Asprosin is the C-terminal cleavage product of profibrillin, encoded by the two terminal exons of FBN1 and released principally by white adipose tissue. Its discovery established it as a fasting-induced glucogenic hormone acting on the hepatocyte through a cyclic AMP-protein kinase A pathway. It was subsequently shown to cross the blood-brain barrier and activate orexigenic AgRP neurons, thereby stimulating appetite and adiposity accrual. Two receptors have been described: the olfactory receptor OLFR734 for the hepatic glucogenic arm and protein tyrosine phosphatase receptor delta for the central orexigenic arm. In humans, circulating asprosin is consistently higher in obesity, insulin resistance, type 2 diabetes and metabolic syndrome, and a meta-analysis across these conditions confirms the association. Interventions that reduce adiposity lower it.

Neuregulin 4 is an epidermal growth factor family ligand of ErbB4, enriched in brown and beige adipose tissue and secreted as an endocrine signal to the liver. It is reduced in rodent and human obesity and protects against hepatic steatosis by suppressing lipogenesis. Hepatic NRG4 signalling constitutes an endocrine checkpoint governing the transition from simple steatosis to steatohepatitis, NRG4 promotes systemic fuel oxidation and a favourable adipokine profile, and exercise induces adipose NRG4 through PPARγ, which then disrupts hepatic cGAS-STING inflammatory signaling. In humans, low circulating NRG4 is associated with metabolic syndrome, subclinical carotid disease and steatotic liver disease in adults and children. The literature is not unidirectional: elevated NRG4 has been reported in diabetes, a meta-analysis of observational studies found no overall case-control difference, and a study with paired hepatic transcriptomic profiling found no difference in steatotic liver disease. This heterogeneity is widely attributed to differences in commercial assay calibration and population, a point that directly shapes the analytical design of the present study.

Only three studies have examined either analyte after metabolic and bariatric surgery. Serum asprosin fell six months after surgery, and pre-operative asprosin was the single independent predictor of six-month excess weight loss. In sleeve gastrectomy, adipose-tissue asprosin was elevated relative to non-obese controls while pre-operative serum asprosin did not discriminate, yet serum asprosin still fell by six months. For NRG4, a single dedicated study found that circulating NRG4 rose during the early post-operative recovery phase, before substantial weight loss, and that Nrg4 knockout blunted the hepatic benefit of sleeve gastrectomy in rodents, establishing the rise as contributory rather than merely correlative.

Four gaps follow. First, the two hormones have never been co-measured in any surgical cohort, so the relationship between the falling glucogenic-orexigenic arm and the rising hepatoprotective arm is uncharacterised. Second, existing surgical data are confined to a pre-operative measurement and a single six-month measurement, which cannot separate a weight-loss-dependent effect from an early effect of the operation. Third, neither analyte has been related to quantified body composition after surgery, only to crude anthropometry. Fourth, post-prandial asprosin dynamics, the physiologically defining feature of the hormone, have never been examined before and after a bariatric operation.

ASPEN-SG is designed to address these gaps.

Inclusion Criteria:

• body mass index of at least 35 kg/m² regardless of the presence
• absence or severity of obesity-related comorbidities
• should be considered at 30-34.9 kg/m² in the presence of metabolic disease

Exclusion Criteria:

• revisional or emergency surgery
• type 1 diabetes or insulin-treated type 2 diabetes
• use within three months of a GLP-1 receptor agonist
• dual GIP/GLP-1 receptor agonist
• SGLT2 inhibitor or thiazolidinedione
• systemic corticosteroid or immunosuppressive therapy
• chronic liver disease of non-metabolic aetiology or cirrhosis
• alcohol intake above 20 g/day in women or 30 g/day in men
• estimated glomerular filtration rate below 60 mL/min/1.73 m²
• FBN1-related connective tissue disorder
• active or recent malignancy
• untreated thyroid
• adrenal or gonadal disorder
• pregnancy or lactation
• any device precluding bioelectrical impedance analysis
• high-sensitivity C-reactive protein above 10 mg/L at baseline