Rare SMIM1 Deletion Is Linked to Lower Energy Use—not Identical Diets
More than two years after the finding was announced, the evidence still supports a specific conclusion rather than the sweeping claim suggested by some headlines. The peer-reviewed study published on June 20, 2024 associated a homozygous 17-nucleotide deletion in SMIM1 with excess weight and lower resting energy expenditure; its direct physiological assessment involved 12 people with the genotype.
The research did not compare people eating identical diets, track their subsequent weight gain or demonstrate an effective treatment. Its continuing value lies in showing how a rare genetic difference may alter energy expenditure—not in proving that a single gene determines what happens after the same meal.
The finding concerns loss of both functional copies
SMIM1 encodes a small membrane protein previously known principally for producing the Vel blood-group antigen. The metabolic finding applies to people who inherited the relevant loss-of-function deletion from both parents and consequently lack functional SMIM1 protein. It should not be generalized to every variation in the gene or to everyone with one deleted copy.
The University of Exeter research summary describes an analysis of nearly 500,000 UK Biobank participants and estimates that about one person in 5,000 lacks both copies; the associated average weight difference was 4.6 kilograms in women and 2.4 kilograms in men.
Higher body mass index, waist circumference and arm fat mass were among the associated measurements. Blood and metabolic characteristics also included higher triglycerides, altered markers of fat-tissue function, elevated liver enzymes and lower thyroid-hormone levels. These were group-level associations, so they do not mean that every person without SMIM1 will have obesity or the same laboratory profile.
Lower energy expenditure offers a mechanism
The most important addition to the population data was a clinical metabolic assessment. Resting energy expenditure was measured through indirect calorimetry, while DXA scanning separated lean mass, fat mass and bone mass. Energy expenditure remained lower after adjustment for lean mass, making a simple difference in muscle quantity an insufficient explanation.
This result provides a plausible route from the deletion to higher average weight. Resting metabolism accounts for energy used to maintain basic functions, so a persistent reduction can shift the balance between energy consumed and energy expended. The research therefore identifies lower expenditure as a likely contributor rather than treating body weight as a direct and unexplained effect of the gene.
The thyroid findings require similar precision. Total thyroid hormones were lower at the group level, but thyroid-stimulating hormone was not significantly different, and the evidence did not establish ordinary thyroid disease as the cause. SMIM1’s wider biological function and its relationship with thyroid regulation remain unresolved.
Why “the same food” is an extrapolation
A controlled feeding study would be needed to test the headline claim directly. Participants with and without functional SMIM1 would have to receive matched energy intake under comparable conditions, with movement, medication and other relevant influences measured or controlled over time. That experiment was not part of the research.
The existing result supports a narrower hypothetical comparison: if two people truly consumed the same amount of energy while one consistently expended less, the latter could retain more energy, all else being equal. Real-world diets, physical activity, sleep, illness and medication rarely remain identical, however, so lower resting expenditure cannot by itself establish what caused an individual weight change.
Nor does the finding overturn energy balance. It helps explain why the expenditure side of that balance can differ biologically between people. The distinction matters because it recognizes a genetic influence without turning the deletion into a guarantee of obesity or a claim that food intake has no effect.
A notable effect with limited population reach
The deletion follows a recessive pattern in this analysis. Metabolic associations were not detected in people carrying only one deleted copy, so ordinary carrier status is not equivalent to lacking functional SMIM1. The relevant two-copy genotype is also uncommon and corresponds to the Vel-negative blood group.
An independent assessment from Science Media Centre Spain judged the work to be strengthened by replication across several populations and by physiological measurements, while stressing that the variant’s rarity makes its contribution to common obesity small.
That limitation separates an important biological subtype from a general explanation of weight gain. Common obesity usually reflects the combined influence of many genetic variants, environment, health conditions, medication, food intake and energy expenditure. A comparatively strong association in a small genetic group can be scientifically useful without accounting for a large share of obesity in the wider population.
The treatment proposal has not become clinical evidence
Because lower thyroid hormones accompanied reduced energy expenditure, thyroid-hormone supplementation was proposed as a treatment worth investigating for people without functional SMIM1. The published work contained no treatment arm, however, and larger physiological studies were considered necessary before a clinical trial could be justified.
This means levothyroxine has not been shown to produce weight loss in this genetic group. The result also provides no basis for using thyroid medication to treat people who retain functional SMIM1 or for interpreting body weight alone as evidence of Vel-negative status.
The durable conclusion is precise: a rare, two-copy SMIM1 deletion is associated with reduced resting energy expenditure, higher average weight and several metabolic differences. Whether people with the deletion gain more weight from an identical diet remains untested, and the proposed targeted therapy remains a research hypothesis.
Also read:
Subscribe to our newsletter
Get the latest Web3, AI, and crypto news delivered straight to your inbox.