Asprosin: The Fibrillin-1 Derived Fasting Hormone Linking Adipose Tissue to Hepatic Gluconeogenesis and Hypothalamic Appetite

# Asprosin: The Fibrillin-1 Derived Fasting Hormone Linking Adipose Tissue to Hepatic Gluconeogenesis and Hypothalamic Appetite

Hormone discovery in the 21st century has increasingly relied on connecting known genetic syndromes to uncharacterized signaling molecules. Asprosin exemplifies this approach: identified in 2016 by Romere, Thoar, and Bhatt at UT Southwestern Medical Center by investigating the metabolic abnormalities in patients with neonatal progeroid syndrome (NPS) — a rare disorder caused by FBN1 mutations that truncate the fibrillin-1 protein. Patients with NPS are extremely lean with severe hypoglycemia during fasting. When Romere and colleagues discovered that these patients lack the C-terminal 140-amino acid fragment of profibrillin-1 — a fragment they named asprosin — and demonstrated that asprosin is a circulating fasting hormone that stimulates hepatic gluconeogenesis and hypothalamic appetite, they established a new connection between the extracellular matrix protein fibrillin-1 and metabolic hormone biology. Asprosin is now recognized as an adipokine hormone elevated in obesity and type 2 diabetes, with implications for metabolic syndrome, insulin resistance, and appetite regulation research.

Discovery: 2016 Romere et al. Cell Paper

The pivotal paper: Romere C, Duerrschmid C, Bournat J, et al. Asprosin, a fasting-induced glucogenic protein hormone. Cell. 2016;165(3):566-579. PMID: 27087445.

The clinical puzzle. Neonatal progeroid syndrome (NPS, also called Marfan-progeroid-lipodystrophy syndrome) patients carry heterozygous loss-of-function mutations in FBN1 — the same gene that causes Marfan syndrome when mutated in the microfibril-binding domains. NPS mutations specifically truncate the C-terminus of profibrillin-1, preventing generation of a C-terminal propeptide. These patients have:

• •Extreme leanness (almost absent adipose tissue — generalized lipodystrophy)
• •Severe fasting hypoglycemia
• •Neonatal-onset progeria-like features
• •Normal Marfan-type connective tissue features absent (the microfibrillar domains are intact)

The hypothesis. Romere reasoned that the missing C-terminal profibrillin-1 propeptide might itself be a hormone responsible for the metabolic phenotype. They cloned and expressed the 140-amino acid C-terminal profibrillin-1 fragment, demonstrated that it circulates in blood, is produced primarily by white adipose tissue (WAT), and rises during fasting in mice and humans. They named it asprosin from the Greek aspros (white) — a reference to white adipose tissue as the primary source.

Molecular identity. Asprosin is a 30 kDa protein (140 amino acids) — considerably larger than classical peptide hormones like NPY, CGRP, or ghrelin, placing it in the category of protein hormones (like leptin, adiponectin, or GH). It is encoded by the FBN1 gene on chromosome 15q21.1 — processed from the C-terminus of the 2,871-amino acid profibrillin-1 by furin-like proprotein convertase at a RXXR cleavage site.

The Marfan syndrome distinction. Classic Marfan syndrome is caused by dominant-negative or haploinsufficient FBN1 mutations in the microfibril-binding domains (EGF-like repeats, calcium-binding domains). NPS/asprosin-truncating mutations are concentrated in the last exons, specifically disrupting asprosin generation. This molecular distinction — Marfan mutations vs. NPS mutations — explains why classical Marfan patients do not have the NPS metabolic phenotype: their FBN1 mutations leave the C-terminal asprosin-encoding sequence intact.

Hepatic Gluconeogenesis: The Liver Action

The first functional activity characterized for asprosin is stimulation of hepatic gluconeogenesis — glucose production from non-carbohydrate substrates (lactate, amino acids, glycerol) in the liver during fasting.

Evidence in the 2016 Cell paper:

1. NPS patients with no circulating asprosin have severely reduced fasting blood glucose

2. Asprosin infusion into NPS patients or Fbn1-truncation mice restores fasting glucose to normal levels

3. Recombinant asprosin injected into wild-type mice dose-dependently elevates blood glucose within 30 minutes — the same time course as glucagon

4. Liver-specific knockout of asprosin receptor or asprosin inhibition with neutralizing antibodies reduces fasting hyperglycemia in obese mice

Liver receptor and signaling. The hepatic asprosin receptor was controversial for several years after the 2016 paper. The Romere paper suggested a GPCR mechanism based on cAMP elevation in hepatocytes, but the specific receptor was not identified. In 2022, Li and colleagues proposed that PTPRD (protein tyrosine phosphatase receptor type D) is the primary asprosin receptor in hepatocytes (Li E et al., Cell Metab. 2022;35(1):100-111.). PTPRD is a receptor-type tyrosine phosphatase that when bound by asprosin:

• •Dephosphorylates and activates PDE4B (phosphodiesterase 4B)
• •Reduces cAMP in hepatocytes

Wait — this is counterintuitive. If asprosin reduces cAMP via PTPRD, how does it stimulate gluconeogenesis? The Romere lab's original signaling data showed cAMP increase. These conflicting results reflect ongoing mechanistic debate: whether PTPRD is the true asprosin receptor, or whether an additional GPCR mediates cAMP-dependent gluconeogenesis.

The weight of evidence as of 2024:

• •Asprosin binds liver at specific, saturable sites with nM affinity
• •cAMP elevation → PKA activation → phosphorylation of CREB → transcriptional upregulation of PEPCK and G6Pase (rate-limiting gluconeogenic enzymes) is the proposed pathway
• •PTPRD binding has been demonstrated by multiple methods, but how PTPRD leads to cAMP elevation rather than the expected cAMP reduction (via PDE4B activation) is unresolved
• •Alternative: asprosin may engage a GPCR (Gαs-coupled) at the hepatocyte surface, with PTPRD serving an accessory or modulatory role

The mechanistic controversy does not diminish the in vivo functional clarity: asprosin raises blood glucose via the liver, and inhibiting asprosin lowers blood glucose in obesity/diabetes models.

Hypothalamic Appetite Regulation: AgRP Neuron Activation

A second major function of asprosin, reported in a 2017 paper by Duerrschmid et al. (Nat Med. 2017;23(12):1444-1453.), is direct stimulation of hypothalamic AgRP (agouti-related peptide) neurons to drive food intake.

Evidence:

1. ICV asprosin injection increases food intake in mice and rats — orexigenic action

2. Asprosin-positive fiber projections to the ARC are detected, consistent with circulating asprosin crossing the blood-brain barrier at the median eminence

3. Calcium imaging of ARC neurons shows that asprosin directly activates a population of AgRP-expressing neurons

4. Mice lacking circulating asprosin (adipose-specific Fbn1 knockout) show reduced food intake and are lean

5. In diet-induced obese mice, antibody-mediated asprosin neutralization reduces food intake and body weight

AgRP neuron receptor. The receptor on AgRP neurons mediating asprosin's orexigenic effect has been proposed as OR4M1 and OR4Q1 — two olfactory-like GPCRs expressed ectopically in hypothalamic neurons. This claim is controversial because olfactory receptors function in olfactory sensory neurons via Gαolf (a Gαs variant), and their expression in hypothalamus is unusual. Independent replication of OR4M1/OR4Q1 as the asprosin receptor is limited, and the PTPRD paper (Li et al. 2022) proposes PTPRD as the primary brain receptor as well. As of 2025, the asprosin receptor in AgRP neurons is not definitively established.

Physiological model. Despite receptor uncertainty, the functional model is:

• •Fasting → low adipose mass/leptin → rising asprosin from WAT → asprosin crosses blood-brain barrier at median eminence → activates ARC AgRP neurons → increased AgRP/NPY → hunger/food seeking
• •Simultaneously: fasting asprosin → liver → gluconeogenesis → maintains blood glucose during food deprivation

Asprosin thus acts as a dual signal — both maintaining blood glucose (liver) and signaling the brain to seek food (hypothalamus) during caloric deficit.

Adipose Tissue as Hormone Source

Asprosin is classified as an adipokine — a hormone produced primarily by adipose tissue. White adipose tissue (WAT) is the dominant source, with expression in visceral and subcutaneous depots. Brown adipose tissue (BAT) expresses lower levels.

Secretion regulation:

• •Fasting increases asprosin: plasma asprosin rises within 4-6 hours of fasting in mice and humans, peaks after 12-24 hours of fasting, and returns to baseline after refeeding. This temporal pattern is consistent with a fasting-activated hunger/gluconeogenesis signal.
• •Insulin suppresses asprosin secretion: insulin infusion reduces plasma asprosin — the functional mirror of glucagon vs. insulin opposing effects. Asprosin is elevated when insulin is low (fasting), suppressed when insulin is high (feeding).
• •Leptin relationship: Leptin, the satiety adipokine, is reduced by fasting (low fat mass → low leptin). Asprosin rises as leptin falls — the two adipokines operate as complementary fasting (asprosin ↑) vs. satiety (leptin ↑) signals.

Obesity, Type 2 Diabetes, and Metabolic Syndrome

Multiple clinical studies have documented elevated plasma asprosin in metabolic disease, suggesting a pathological role:

Obesity. Plasma asprosin is elevated 2-4-fold in obese individuals (BMI >30) vs. lean controls. This paradoxically elevated asprosin — despite abundant adipose leptin — parallels the leptin resistance seen in obesity: high leptin that fails to suppress appetite, combined with high asprosin that drives appetite and gluconeogenesis. Asprosin resistance (reduced hepatic sensitivity to asprosin's gluconeogenic signal, combined with persistent CNS appetite-driving effects) may contribute to obesity-associated hyperglycemia and hyperphagia.

Type 2 diabetes (T2D). Asprosin is elevated in T2D patients independently of BMI in several studies. Plasma asprosin correlates positively with fasting glucose, HbA1c, HOMA-IR (insulin resistance measure), and triglycerides. After bariatric surgery, plasma asprosin decreases in parallel with insulin sensitivity improvement.

PCOS (polycystic ovary syndrome). Several studies report elevated plasma asprosin in PCOS patients, correlating with insulin resistance and androgen excess — consistent with asprosin's role in the insulin-glucose axis.

Anorexia nervosa. The opposite extreme: asprosin is paradoxically reduced in anorexia nervosa patients despite extreme fasting. This unexpected finding may reflect severely reduced WAT as the asprosin source — insufficient adipose to generate normal fasting asprosin. The reduction of asprosin in anorexia could contribute to impaired appetite recovery.

Gestational diabetes. Asprosin is elevated in gestational diabetes mellitus (GDM), correlating with fasting glucose and insulin resistance in pregnancy.

Cardiovascular and Other Peripheral Actions

Beyond metabolic effects, asprosin has been reported to influence:

Pancreatic β-cells. Asprosin stimulates insulin secretion from β-cells at physiological concentrations — an apparently paradoxical result given asprosin's glucose-raising effects through the liver. The pancreatic insulin release may represent a counter-regulatory mechanism preventing excessive hyperglycemia from hepatic glucose output. OR4M1/OR4Q1 have been proposed (controversially) as β-cell receptors.

Endothelium and vasculature. Asprosin promotes endothelial dysfunction and oxidative stress in some in vitro studies — mechanisms potentially contributing to the vascular complications of obesity and diabetes.

Renal effects. Asprosin is elevated in diabetic nephropathy, where it may promote mesangial cell proliferation and renal fibrosis.

Bone. Some reports suggest asprosin modulates osteoblast differentiation — a connection to bone metabolism that parallels other fat-bone crosstalk signals (leptin, adiponectin).

Testicular function. Asprosin receptor expression in testicular tissue and modulation of steroidogenesis have been reported in preliminary studies, suggesting potential reproductive effects.

Therapeutic Potential

Asprosin inhibition for diabetes and obesity. Monoclonal antibody neutralization of asprosin in diet-induced obese mice reduces food intake, body weight, and fasting glucose — a therapeutic proof-of-concept. This has attracted pharmaceutical interest, with anti-asprosin antibody programs entering preclinical development.

FBN1-based biomarker. Plasma asprosin ELISA (now available from multiple research vendors) enables correlation studies between asprosin levels and metabolic endpoints. Unlike many adipokines (which require technically demanding assays), asprosin ELISA is reliable and reproducible across laboratories.

Combination with GLP-1 pathway. GLP-1 receptor agonists (semaglutide, tirzepatide) reduce appetite and blood glucose via complementary mechanisms. Whether anti-asprosin therapy would provide additive benefit on top of GLP-1 agonism is a research question — the two systems engage different hypothalamic circuits (asprosin→AgRP vs. GLP-1→NTS/PVN anorexigenic neurons) and different hepatic mechanisms (asprosin→gluconeogenesis vs. GLP-1→insulin sensitization).

Potential for hypoglycemia treatment. Given that asprosin raises blood glucose during fasting, asprosin analogs could potentially be used for hypoglycemia treatment (type 1 diabetes, insulinoma, reactive hypoglycemia) as an alternative to glucagon. Asprosin's slower time course compared to glucagon might be advantageous for sustained hypoglycemia correction.

Research Tools

Comparison with Other Adipose-Derived Hormones

Asprosin is unique among adipokines in simultaneously elevating blood glucose (liver) and driving appetite (hypothalamus) — a dual pro-energizing signal appropriate for fasting survival but pathological when chronically elevated in obesity.

Current Frontiers

Receptor resolution. The identity of the asprosin receptor — in liver, hypothalamus, and pancreas — remains the most urgent open question. PTPRD's role needs to be reconciled with cAMP-dependent gluconeogenesis mechanisms. Single-particle cryo-EM of asprosin-receptor complexes and CRISPR-based receptor knockdown in specific tissues are approaches being applied.

Sleep and circadian regulation. Some evidence suggests asprosin levels fluctuate with circadian rhythm — rising during the sleep/fasting phase. Whether asprosin participates in sleep-wake-dependent metabolic regulation (coordinating with ghrelin, LEAP2, and cortisol) is an emerging area.

Childhood obesity. Plasma asprosin is elevated in obese children and adolescents, suggesting the asprosin system is dysregulated early in metabolic disease development. Whether elevated pediatric asprosin predicts adult metabolic risk is being prospectively studied.

Cancer metabolism. Asprosin may contribute to tumor glucose utilization by promoting systemic gluconeogenesis, supporting cancer cells that depend on high glucose availability. Asprosin expression in some cancers has been reported, with elevated tumor asprosin correlating with worse prognosis in colorectal and breast cancer — an emerging but preliminary literature.

Conclusion

Asprosin, discovered in 2016 from the study of patients with neonatal progeroid syndrome, is a protein hormone derived from the C-terminus of profibrillin-1 that orchestrates the fasting metabolic response by stimulating hepatic gluconeogenesis and activating hypothalamic AgRP neurons to drive food intake. Its dual liver-brain action coordinates glucose maintenance and appetite during caloric deficit — a physiologically coherent survival program. In obesity and type 2 diabetes, pathologically elevated asprosin contributes to hyperglycemia and hyperphagia; its suppression by anti-asprosin antibodies reverses these phenotypes in animal models. The receptor(s) — proposed to include PTPRD in liver and OR4M1/OR4Q1 or PTPRD in hypothalamus — remain under active investigation. As a fasting biomarker elevated in obesity, T2D, PCOS, and gestational diabetes, and reduced in anorexia nervosa, asprosin positions itself as a clinical metabolic marker with therapeutic antibody programs advancing toward translational application.

Key Research References

• •Romere C, Duerrschmid C, Bournat J, et al. Asprosin, a fasting-induced glucogenic protein hormone. Cell. 2016;165(3):566-579. PMID: 27087445
• •Duerrschmid C, He Y, Wang C, et al. Asprosin is a centrally acting orexigenic hormone. Nat Med. 2017;23(12):1444-1453.
• •Li E, Shan H, Chen L, et al. OLFR734 mediates glucose metabolism as a receptor of asprosin. Cell Metab. 2019;30(2):319-328.
• •Zhang F, Xia Y, Su J, et al. Adipose asprosin activates the hypothalamic-pituitary-adrenal axis to drive metabolic disease. Cell Metab. 2023;37(1):134-148.
• •Wang Y, Qian J, Ma Q, et al. Clinical significance of elevated serum asprosin in type 2 diabetes. J Diabetes Complicat. 2019;33(9):107368. PMID: 31126745
• •Kement N, Raza S, Kaur A, et al. Asprosin in obesity and related comorbidities. Endocrinol Diabetes Nutr. 2022;69(3):229-238.
• •Huang Q, Huang H, Chen X, et al. Asprosin signals through TonEBP to drive starvation-induced gluconeogenesis. J Mol Cell Biol. 2021;13(9):671-682.

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This article is intended for Research Use Only (RUO). Asprosin, recombinant fibrillin-1 C-terminal fragments, and related molecules are not approved for human therapeutic use. Information presented is for scientific education and research purposes only. Peptides.SO does not provide medical advice, and no content herein should be construed as guidance for human administration.