PCSK1 Obesity: Two GLP-1 Cases

Two sisters in their thirties with a loss-of-function PCSK1 mutation lost 16% to 27% of their initial body weight during treatment with semaglutide and tirzepatide. Both had class III obesity, with starting body mass indexes of 42 and 46 kg/m2^[1]. The response is clinically notable, but two case reports cannot establish how people with PCSK1-related obesity generally respond to either medicine.

What the cases reported

The report, published online in Obesity Facts on October 12, 2026, describes two adult sisters referred for obesity treatment. Each carried a loss-of-function mutation in PCSK1, the gene that encodes prohormone convertase 1/3. Neither woman had an obesity-related disease at referral, according to the abstract, despite severe obesity. Treatment involved the GLP-1 receptor agonist semaglutide and the dual GIP and GLP-1 receptor agonist tirzepatide^[1][2].

Details are limited. The published abstract gives the combined weight-loss range without enough patient-level information to compare the sisters, draw a head-to-head conclusion about semaglutide versus tirzepatide, or show that the PCSK1 mutation predicted the magnitude of response. The value of the cases is narrower: meaningful weight loss occurred despite a disrupted pathway that might have been expected to alter how these therapies work^[1].

Why PCSK1 matters

PCSK1 makes an enzyme that cuts inactive hormone precursors into active hormones and neuropeptides. Its substrates include proinsulin and proglucagon as well as proopiomelanocortin, usually shortened to POMC. When both copies of PCSK1 lose function, severe obesity can occur alongside digestive and endocrine problems^[3].

POMC belongs to the leptin-melanocortin system, a brain pathway involved in hunger and energy balance. PCSK1 helps process POMC into signals that act farther down that pathway. A damaging mutation can therefore interrupt a biological route strongly tied to early and severe obesity. That is why a substantial response to GLP-1-based treatment carries mechanistic interest beyond these two patients^[1][3].

PCSK1 deficiency is broader than a body-weight diagnosis. Published reviews describe malabsorptive diarrhea and disturbed glucose control, with thyroid, adrenal, or reproductive hormone problems in some patients. The clinical range is wide because not every variant produces the same loss of enzyme activity, and a gene name by itself cannot predict treatment response. Results from one family need especially careful boundaries^[3].

What the response may suggest

The authors interpret the cases as evidence that GLP-1-based therapies may influence weight through actions both upstream and downstream of POMC. In plain language, an intact POMC route may not be the only way these medicines affect appetite or body weight. Semaglutide activates the GLP-1 receptor. Tirzepatide activates both GIP and GLP-1 receptors, so its response cannot be assigned to GLP-1 signaling alone^[1].

The mechanism remains uncertain. PCSK1 processes several precursors, the effect of a specific variant depends on how much enzyme activity remains, and two related patients share background genetics and parts of their environment. Without detailed functional testing and a comparison group, the report cannot locate the response at a specific point in the pathway^[1][3].

The cases do show why rare genetic obesity should not automatically be treated as resistance to every established obesity medicine. They also argue against assuming that one disrupted signaling step explains the whole clinical response. Readers can review the two medicines separately on our semaglutide page and tirzepatide page.

What two cases cannot answer

There was no control group. Weight can change with treatment and accompanying care, and the abstract does not isolate those contributions from illness or other factors that unfolded during the same period. The sisters' response also cannot estimate an average effect or the chance of an adverse event. A range of 16% to 27% should not be presented as an expected result for another person with the same gene^[1].

Related participants are informative because the shared mutation is rare, but the family relationship also narrows generalizability. The sisters may share other genetic variants, early-life exposures, eating environments, or patterns of clinical support. A series drawn from unrelated patients would help researchers see whether the response travels with the PCSK1 defect or with features particular to this family^[1].

The report does not justify choosing one drug over another or prescribing a particular dose. Semaglutide and tirzepatide have different receptor targets, labels, contraindications, and safety information. Genetic findings add clinical context but do not replace an individualized review by clinicians familiar with endocrine genetics and obesity medicine. Our tirzepatide regulation section covers approval status by jurisdiction.

The next research question

A useful follow-up would enroll more people with confirmed pathogenic PCSK1 variants and document the residual function of each variant. Using one common protocol, researchers could follow hunger and body weight over time while collecting metabolic measures and adverse events, then compare responses across semaglutide, tirzepatide, and treatments that directly target the melanocortin pathway^[1][3].

For now, these sisters provide a biological clue rather than a treatment rule. Their weight loss shows that a loss-of-function PCSK1 mutation did not prevent a large response in these individual cases. It leaves open which receptor actions produced that response, how durable it will be, and whether the observation applies to other PCSK1 variants or patients^[1].