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Researchers map how a single protein builds the calorie-burning infrastructure inside brown fat

Researchers map how a single protein builds the calorie-burning infrastructure inside brown fat

New Capabilities
By Newzino Staff |

NYU-led team identifies SLIT3 pathway with multiple drug targets, opening an energy-expenditure approach to obesity distinct from appetite-suppressing GLP-1 drugs

Yesterday: Nature Communications publishes SLIT3 brown fat pathway discovery

Overview

Every obesity drug on the market works by suppressing appetite — making people eat less. A team led by NYU researcher Farnaz Shamsi has now mapped a completely different route: a protein called SLIT3 that gets sliced in two by an enzyme, with each half independently building the blood vessels and nerve wiring that brown fat needs to burn calories as heat. The discovery, published in Nature Communications and validated in tissue from more than 1,500 people, identifies multiple molecular targets that could be turned into drugs.

Why it matters

If brown fat can be made to burn more calories, obesity treatment gains an entirely new mechanism beyond appetite suppression.

Key Indicators

1,500+
Human tissue samples analyzed
Researchers validated the pathway in fat tissue from over 1,500 individuals, including people with obesity.
5+
Druggable molecular targets identified
SLIT3 itself, its two fragments (N-terminal and C-terminal), the BMP1 enzyme, and the PLXNA1 receptor.
~$100B
GLP-1 obesity drug market (2025)
The current appetite-suppression market that an energy-expenditure approach could complement or compete with.
0
Approved brown-fat-activating obesity drugs
Despite 17 years of research since brown fat's rediscovery in adults, no drug targeting this mechanism has reached market.

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People Involved

FS
Farnaz Shamsi
Leading SLIT3/brown fat research program at NYU
 Paul Cohen
Paul Cohen
Active collaborator on SLIT3 research

Organizations Involved

NYU College of Dentistry
NYU College of Dentistry
Academic Research Institution
Home institution of senior author and primary research team

NYU's dental college houses the molecular pathobiology department where Shamsi's lab conducts brown fat metabolism research.
Nature Communications
Nature Communications
Scientific Journal
Published the peer-reviewed SLIT3 study

A high-impact open-access journal in the Nature portfolio that publishes research across the natural sciences.

Timeline

  1. Nature Communications publishes SLIT3 brown fat pathway discovery

    Publication

    The peer-reviewed study reveals that the protein SLIT3 is cleaved by the enzyme BMP1 into two fragments — one that builds blood vessel networks and another that builds nerve networks in brown fat — with validation in tissue from over 1,500 people. Multiple druggable targets are identified.

  2. Shamsi lab posts SLIT3 preprint on bioRxiv

    Research

    The NYU team posted preliminary findings on the SLIT3 pathway in brown fat as a preprint, beginning peer review.

  3. 52,000-patient study links brown fat to protection against chronic disease

    Research

    Paul Cohen's team at Rockefeller University analyzed 130,000 PET scans and found that obese people with detectable brown fat had diabetes and heart disease rates comparable to non-obese people — the strongest human evidence yet that brown fat matters clinically.

  4. Chronic mirabegron improves metabolism but fails to produce weight loss

    Clinical trial

    Studies showed mirabegron improved brown fat activity, HDL cholesterol, and insulin sensitivity in obese patients, but produced no significant weight loss — a blow to the beta-3 agonist approach.

  5. Mirabegron shown to activate human brown fat, but with side effects

    Clinical trial

    Aaron Cypess and colleagues at the National Institutes of Health demonstrated that mirabegron, a bladder drug, activated brown fat in humans. However, the effective dose was four times the approved amount and raised heart rate and blood pressure.

  6. Three landmark papers prove adults have active brown fat

    Discovery

    The New England Journal of Medicine published three papers by Cypess, Virtanen, and van Marken Lichtenbelt using PET-CT scans to demonstrate that functional brown adipose tissue exists in adult humans — overturning decades of assumption that it disappeared after infancy.

Scenarios

1

SLIT3-based drug enters clinical trials within five years

Discussed by: Drug Discovery World, Neuroscience News (both highlighting the multiple druggable targets)

A biotech company or academic group develops a recombinant SLIT3 fragment, a BMP1 modulator, or a PLXNA1 agonist and advances it into Phase I trials. The pathway's validation in 1,500+ human samples and multiple identified targets make it attractive for early-stage drug development. This is the most optimistic realistic path, though typical timelines from basic discovery to first-in-human dosing average 5-7 years.

2

Brown fat infrastructure approach combined with GLP-1 drugs in clinical studies

Discussed by: Obesity researchers noting the complementary mechanisms (energy expenditure + appetite suppression)

Rather than a standalone therapy, the SLIT3 pathway is developed as a combination approach alongside existing GLP-1 receptor agonists. Increasing brown fat calorie burning while simultaneously reducing appetite could produce weight loss exceeding what either mechanism achieves alone, and potentially reduce the lean mass loss seen with GLP-1 drugs alone.

3

Pathway stalls in translation from mice to humans, joining long list of brown fat disappointments

Discussed by: Historical pattern noted by multiple review papers on BAT therapeutics

The SLIT3 findings, like mirabegron, irisin, and beta-3 agonists before them, prove difficult to translate into humans. Adult human brown fat depots may be too small, the pathway may be already maximally engaged or resistant in obese patients, or the effect on total energy expenditure may be too modest. The history of brown fat therapeutics strongly favors caution — every previous approach has stalled at the translational stage.

4

Discovery sparks new wave of brown fat biotech investment

Discussed by: Drug Discovery World reporting on the therapeutic implications

The identification of five-plus druggable targets in a single pathway, combined with large-scale human validation, reignites investor interest in brown fat therapeutics — a field that went dormant after earlier failures. A new wave of startups or pharma partnerships forms around SLIT3 biology, even if clinical results remain years away.

Historical Context

Leptin discovery and the obesity drug disappointment (1994)

December 1994

What Happened

Jeffrey Friedman at Rockefeller University cloned the ob gene and its protein leptin, revealing for the first time that fat tissue secretes a hormone regulating body weight. The ob/ob mouse, which lacked leptin, was massively obese; injecting leptin caused dramatic weight loss. Amgen licensed the rights for $20 million and rushed to clinical trials.

Outcome

Short Term

Leptin administration had minimal effect in most obese humans, who already had high leptin levels and were resistant to it. The drug failed as a general obesity therapy.

Long Term

Leptin reshaped the entire field's understanding of adipose tissue as an endocrine organ. It eventually found a niche treating rare congenital leptin deficiency. The failure taught researchers that a pathway proven in mice can work entirely differently in obese humans.

Why It's Relevant Today

The SLIT3 discovery faces the same translational question: will a mechanism validated in mice and in human tissue samples hold up when tested as a drug in living obese patients? The 1,500-person tissue analysis is a stronger starting point than leptin had, but the history counsels caution about the gap between biological insight and therapeutic impact.

Mirabegron brown fat trials (2015-2020)

2015-2020

What Happened

Aaron Cypess at the National Institutes of Health tested mirabegron, an already-approved bladder drug that activates beta-3 adrenergic receptors, as a brown fat activator. At four times the approved dose, it lit up brown fat on PET scans and raised resting metabolic rate by about 200 calories per day — the most successful chemical activation of human brown fat to date.

Outcome

Short Term

Chronic treatment improved insulin sensitivity, HDL cholesterol, and brown fat metabolic activity. But it produced no significant weight loss and caused cardiovascular side effects at effective doses.

Long Term

The result proved brown fat can be pharmacologically activated in humans but suggested that simply switching it on isn't enough. The tissue may need structural enhancement — more blood vessels, more nerve connections — to burn calories at a meaningful scale.

Why It's Relevant Today

Mirabegron's failure is precisely the problem Shamsi's SLIT3 research addresses. Rather than trying to flip brown fat's activation switch, the new approach builds the vascular and neural infrastructure the tissue needs to function. It's a direct response to the lesson mirabegron taught.

GLP-1 receptor agonist development (1987-2021)

1987-2021

What Happened

Jens Juul Holst at the University of Copenhagen characterized glucagon-like peptide-1's role in insulin secretion in 1987. The first GLP-1 drug, exenatide (derived from Gila monster venom), reached market in 2005 for diabetes. Over the next 16 years, iterative improvements led to semaglutide (Wegovy, approved 2021) achieving 15-17% weight loss — transforming obesity from an intractable condition into a treatable one.

Outcome

Short Term

GLP-1 drugs became the fastest-growing drug class in history, with semaglutide and tirzepatide generating tens of billions in annual revenue.

Long Term

The 34-year journey from basic science to blockbuster drug showed that obesity pathways require patient, iterative development. But GLP-1 drugs cause significant lean mass loss and weight regain upon stopping, leaving room for complementary approaches.

Why It's Relevant Today

The SLIT3 pathway is at the very beginning of a development arc that took GLP-1 drugs three decades to complete. The realistic timeline to a brown fat drug, if the pathway holds, is measured in years to decades — not months. But the GLP-1 precedent also shows that a fundamentally new mechanism can eventually reshape an entire therapeutic category.

Sources

(8)
+2
Nature Communications ScienceDaily Neuroscience News bioRxiv Rockefeller University News Journal of Clinical Investigation Drug Discovery World Medical Xpress