Energy expenditure and thermogenesis

GLP-1 (native; Physiology) MARKETED

Energy expenditure and thermogenesis No change

Very low evidence

Rodent EE-defence reframe (Jacobsen Cell Rep 2024): standard ~22C mouse housing is a cold stress inflating energy expenditure, but independent of ambient temperature...

Jacobsen JM, Petersen N, Torz L, et al. GLP-1 and FGF21 prevent the reduction in metaboli... Source

Full findingRodent EE-defence reframe (Jacobsen Cell Rep 2024): standard ~22C mouse housing is a cold stress inflating energy expenditure, but independent of ambient temperature GLP-1 and FGF21 prevented the FALL in metabolic rate caused by weight loss. This reframes the question from EE-elevation to EE-DEFENCE during deficit. It is a rodent, hypothesis-tier finding - NOT retatrutide-direct - and its human translation is indeterminate.

PopulationMice across 22C vs thermoneutral 30C housing, GLP-1/FGF21 (and MC4R/PYY/GDF15) weight-loss models (Cell Rep 2024;43(8):114501)

Fundingindustry - Novo Nordisk (study performed by Novo Nordisk; authors are Novo Nordisk employees, paper funding/affiliation line)

Scope limitsanimal data; human relevance uncertain; thermoneutrality vs 22C housing reframe; not retatrutide-direct

Comparatorsvehicle / weight-loss control; thermoneutral vs 22C housing

GLP-1 RA class MARKETED

Energy expenditure and thermogenesis Mixed

Low evidence

Scoping review of human EE studies (23 studies): acute or chronic GLP-1RA MONOtherapy does not appear to impact energy expenditure independent of weight loss....

Vieira FT, Deng Z, Muller MJ, et al. Effects of GLP-1 Receptor Agonists (Mono and Combina... Source

Full findingScoping review of human EE studies (23 studies): acute or chronic GLP-1RA MONOtherapy does not appear to impact energy expenditure independent of weight loss. Combination with glucagon produced varied impacts on EE components (RQ, RMR, sleep metabolic rate); combination with GIP decreased RQ and increased fat utilisation. Eight studies (34.8%) concluded non-significant EE effects; 11 (47.8%) were inconclusive due to statistical analyses. Most assessed RMR; only 4 used 24-h whole-room calorimetry; none used doubly labelled water.

PopulationScoping review, humans, inception to Oct 2025; 23 studies (10 monotherapy: 4 exenatide, 4 liraglutide, 1 semaglutide, 1 beinaglutide; 13 combination: 11 dual, 2 triple agonists)

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitsClass-level landmark for the 'whole-body-EE-null' pole in humans. Note the differential signal: +GIP lowers RQ/raises fat oxidation (matches the tirzepatide fat-oxidation finding, C-TIRZEPATIDE-EE-03), while +glucagon affects EE components variably. Co-author Heymsfield (Pennington). Per PubMed.

Comparatorsplacebo; across-study heterogeneity

Retatrutide INVESTIGATIONAL

Energy expenditure and thermogenesis Not directional

Very low evidence

Glucagon-mediated increased energy expenditure is PROPOSED for retatrutide (mechanistic/preclinical reviews); not measured in the cited human phase-2 trial.

Jastreboff AM, Kaplan LM, Frias JP, et al. Triple-Hormone-Receptor Agonist Retatrutide fo... Source

PopulationPreclinical (rodent) models with calorie-intake-matched controls; reported via reviews/secondary sources

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitsanimal data; human relevance uncertain; magnitude web/secondary-sourced

Comparatorscalorie-intake-matched control

Retatrutide INVESTIGATIONAL

Energy expenditure and thermogenesis Increase

Moderate evidence

FOLK-CLAIM VERDICT ('retatrutide runs hot / sweating / feels hot, via glucagon'): MIXED - the MECHANISM is real and plausibly reta-distinct (glucagon thermogenesis is...

Salem V et al. Glucagon increases energy expenditure independently of brown adipose tissu... Source

Full findingFOLK-CLAIM VERDICT ('retatrutide runs hot / sweating / feels hot, via glucagon'): MIXED - the MECHANISM is real and plausibly reta-distinct (glucagon thermogenesis is textbook human physiology, and reta is the only glucagon-arm agent in late development), but the reta-DIRECT evidence is thin-to-absent (no controlled thermometry/sweating measurement; not a prominent named AE in phase-2). So the 'runs hot' symptom is INFERRED from the mechanism, not demonstrated in patients.

PopulationHuman glucagon-infusion thermogenesis study (Salem 2016) for the mechanism; reta phase-2 obesity/T2D trials (no temperature endpoint) for the direct-data gap.

Fundingacademic-MRC/BBSRC/NIHR/Wellcome Trust

Scope limitsGRADE: mechanism moderate (human infusion study); reta-direct symptom UNPROVEN (not measured). Belief-vs-reality: this folk attribution is mechanistically MORE credible than most, but the leap to 'reta raises body temperature in patients' is inferred, not shown - do not state as a documented clinical effect. Links the glucagon-thermogenesis mechanism (energy-expenditure threads) to the lay claim. Cross-ref C-RETATRUTIDE-SAFETY-DYSESTHESIA-01 (the other reta-distinct sensory/autonomic signal).

Comparatorsplacebo

Semaglutide MARKETED

Energy expenditure and thermogenesis Decrease

Moderate evidence

FDA Ozempic Clinical Pharmacology review: in obese non-diabetics semaglutide weight loss was driven by ~24% lower energy intake, NOT energy expenditure - resting...

FDA Ozempic NDA 209637 Clinical Pharmacology Review, Reference ID 4142722, Study NN9535-3685 Source

Full findingFDA Ozempic Clinical Pharmacology review: in obese non-diabetics semaglutide weight loss was driven by ~24% lower energy intake, NOT energy expenditure - resting metabolic rate was significantly lower on semaglutide (-601.9 kJ/24h), and the reviewer concluded weight loss is more related to appetite/intake than to expenditure. Supports 'EE not demonstrably raised (chronic GLP-1-mono)', NOT a causal EE-suppression claim: the post-hoc lower RMR is mass-confounded (lower RMR is the trivial consequence of lower mass).

PopulationObese non-diabetic adults, Study NN9535-3685 (FDA NDA 209637 ClinPharm PD section, p.45-47)

Fundingindustry - Novo Nordisk (applicant/manufacturer; FDA Clinical Pharmacology review of Novo's NDA 209637 submission)

Scope limitspost-hoc / exploratory RMR-intake analysis; mass-confounded (lower RMR tracks lower mass)

Comparatorsplacebo

Semaglutide MARKETED

Energy expenditure and thermogenesis Increase

Very low evidence

In diet-induced obese rats with a pair-fed (intake-matched) control, semaglutide produced weight loss beyond caloric restriction alone and, across adipose depots,...

Byun S, Sotzen MR, Knappenberger MA, et al. Advantage of Semaglutide: Comprehensive Analy... Source

Full findingIn diet-induced obese rats with a pair-fed (intake-matched) control, semaglutide produced weight loss beyond caloric restriction alone and, across adipose depots, promoted white adipose tissue browning, smaller adipocytes and enhanced sympathetic innervation - changes largely absent in pair-fed rats. Semaglutide rescued caloric-restriction-associated hypothermia, reduced the small fall in circulating thyroid hormones, potentiated local thyroid input, and sustained increased locomotor activity. Effects were more potent in females.

PopulationDiet-induced obese rats; semaglutide vs ad libitum control vs intake-matched (pair-fed); sex-stratified

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitsanimal data; human relevance uncertain

Comparatorsad libitum control; pair-fed control

Semaglutide MARKETED

Energy expenditure and thermogenesis Increase

Moderate evidence

In a small human study (T2DM, subcutaneous fat biopsy before and after 6-month semaglutide), therapy restored adipose-derived stem cell proliferation and increased...

Stafeev I, Agareva M, Michurina S, et al. Semaglutide 6-months therapy of type 2 diabetes... Source

Full findingIn a small human study (T2DM, subcutaneous fat biopsy before and after 6-month semaglutide), therapy restored adipose-derived stem cell proliferation and increased both white and beige adipogenesis ex vivo, with lipid-droplet fragmentation in beige adipocytes. Newly formed beige adipocytes used glucose for canonical thermogenesis; both white and beige adipocytes showed 2-3 fold higher glucose uptake. Insulin sensitivity (HOMA-IR, M-index) was unchanged.

PopulationT2DM patients, N=8, subcutaneous adipose biopsy at baseline and after 6 months semaglutide; adipose-derived stem cells studied ex vivo

Fundingacademic-Russian Science Foundation (grant 22-15-00365)

Scope limitssmall sample (N~8)

Comparatorswithin-subject baseline

Tirzepatide MARKETED

Energy expenditure and thermogenesis Increase

Very low evidence

FDA Mounjaro Pharm/Tox review (rodent lead): in diet-induced-obese mice tirzepatide raised metabolic rate more than semaglutide and, at pair-fed/body-weight-matched...

FDA Mounjaro NDA 215866 Pharmacology/Toxicology Review, Reference ID 4953686 (reviewer Br... Source

Full findingFDA Mounjaro Pharm/Tox review (rodent lead): in diet-induced-obese mice tirzepatide raised metabolic rate more than semaglutide and, at pair-fed/body-weight-matched doses, still produced greater glucose infusion rate and tissue glucose uptake - an intake-independent metabolic component. This is a RODENT mechanistic lead in the GIP arm, NOT the glucagon arm, and does NOT translate to a human intake-independent energy-expenditure claim (22C cold-stress EE inflation; poor mouse-GIPR translation; contradicted by human RMR/TEE).

PopulationDIO mice (FDA NDA 215866 Pharm/Tox in-vivo studies, Figs 3,4,7); standard ~22C housing; pair-fed / body-weight-matched comparisons

Fundingindustry - Eli Lilly (applicant/manufacturer; FDA Pharm/Tox review of Lilly's NDA 215866 submission)

Scope limitsanimal data; human relevance uncertain

Comparatorssemaglutide; pair-fed control

Tirzepatide MARKETED

Energy expenditure and thermogenesis Increase

Low evidence

In premenopausal women with obesity, 24 weeks of tirzepatide increased the proportion of participants with cold-stimulated PET/CT-detectable brown adipose tissue (BAT)...

Herman R et al., TABFAT trial, presented at ENDO 2026 (Endocrine Society annual meeting),... Source

Full findingIn premenopausal women with obesity, 24 weeks of tirzepatide increased the proportion of participants with cold-stimulated PET/CT-detectable brown adipose tissue (BAT) activity from 41.2% to 64.7%, with no comparable change in the placebo group; cold-stimulated BAT activity and volume also increased (absolute changes greater vs placebo). MRI assessment was consistent with FDG-PET/CT. Signs of white subcutaneous fat converting to 'beige' fat were also reported.

PopulationTABFAT trial; N=34 premenopausal women with obesity, median age 39 y, median BMI 36.9 kg/m2; randomised 1:1 tirzepatide vs placebo; 24 weeks; cold-stimulated 18F-FDG-PET/CT, MRI, infrared thermography

Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)

Scope limitsno outcome data yet (ongoing); small sample (N~34)

Comparatorsplacebo

Tirzepatide MARKETED

Energy expenditure and thermogenesis Not directional

Very low evidence

Design/rationale paper for the TABFAT trial: investigator-initiated RCT evaluating tirzepatide effects on BAT volume/activity (18F-FDG-PET/CT, MRI, infrared...

Herman R, Jensterle M, Horvat S, et al. Effect of tirzepatide-induced weight loss on adip... Source

Full findingDesign/rationale paper for the TABFAT trial: investigator-initiated RCT evaluating tirzepatide effects on BAT volume/activity (18F-FDG-PET/CT, MRI, infrared thermography) and WAT browning (subcutaneous adipose mRNA expression and histomorphometry) in premenopausal women with obesity, with whole-body composition and resting energy expenditure as secondary outcomes.

PopulationProtocol; 34 premenopausal women with obesity; registered ClinicalTrials.gov 2025-03-25

Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)

Scope limitsProtocol/design paper (PMC12374325, open access). Per PubMed. The results were presented at ENDO 2026 (C-TIRZEPATIDE-EE-01).

Comparatorsplacebo

Tirzepatide MARKETED

Energy expenditure and thermogenesis Mixed

Low evidence

Phase 1 human study with whole-room indirect calorimetry: tirzepatide did NOT attenuate weight-loss-induced metabolic adaptation (no detectable preservation of...

Ravussin E, Sanchez-Delgado G, Martin CK, et al. Tirzepatide did not impact metabolic ada... Source

Full findingPhase 1 human study with whole-room indirect calorimetry: tirzepatide did NOT attenuate weight-loss-induced metabolic adaptation (no detectable preservation of sleeping or 24-h energy expenditure) but DID increase fat oxidation (reduced respiratory exchange ratio) vs placebo, alongside reduced appetite and ad libitum calorie intake. In the paired preclinical study (calorie-restricted obese mice), tirzepatide reduced the drop in energy expenditure seen in vehicle/pair-fed mice (i.e. attenuated metabolic adaptation) and lowered RER.

PopulationPhase 1 RCT in people with obesity (NCT04081337) plus preclinical calorie-restricted obese mice with pair-fed control

Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)

Scope limitsanimal data; human relevance uncertain

Comparatorsplacebo; pair-fed control (mice)

Tirzepatide MARKETED

Energy expenditure and thermogenesis Increase

Very low evidence

In high-fat-diet obese mice with a pair-fed control arm, tirzepatide exerted distinct effects on brown adipose tissue relative to white: significantly boosting BAT...

Mestres-Arenas A, Quesada-Lopez T, Blasco-Roset A, Giralt M, Villarroya F, Planavila A, P... Source

Full findingIn high-fat-diet obese mice with a pair-fed control arm, tirzepatide exerted distinct effects on brown adipose tissue relative to white: significantly boosting BAT thermogenic activity and upregulating genes linked to thermogenesis and substrate oxidation, while white adipose tissue was primarily affected in lipid metabolism. These BAT effects were specific to tirzepatide and NOT attributable to reduced food intake (pair-fed mice did not show them).

PopulationHFD-induced obese mice; tirzepatide vs pair-fed control (matched body-weight loss)

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitsanimal data; human relevance uncertain

Comparatorspair-fed control

Tirzepatide MARKETED

Energy expenditure and thermogenesis Increase

Very low evidence

In HFD-obese mice and in 3T3-L1 adipocytes, tirzepatide promoted browning of white adipose tissue via the cAMP-PGC-1alpha-UCP1 signalling axis, reducing intracellular...

Sun Y, Xia Y, Ge W, Li Q. Tirzepatide reduces intracellular lipid content by promoting th... Source

Full findingIn HFD-obese mice and in 3T3-L1 adipocytes, tirzepatide promoted browning of white adipose tissue via the cAMP-PGC-1alpha-UCP1 signalling axis, reducing intracellular lipid droplet accumulation. Increased browning markers (PGC-1alpha, UCP1) were confirmed in vivo; in vitro the adenylyl cyclase inhibitor SQ22536 attenuated the effect, implicating cAMP-dependent signalling. Described as a direct, adipocyte-intrinsic mechanism beyond central appetite regulation.

PopulationHFD-induced obese mice (in vivo, RNA-seq) and differentiated 3T3-L1 adipocytes (in vitro, +/- SQ22536)

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitsanimal data; human relevance uncertain

Comparatorsvehicle; SQ22536 (cAMP inhibitor, in vitro)

Tirzepatide MARKETED

Energy expenditure and thermogenesis Increase

Very low evidence

In male mice, intracerebroventricular (i.c.v.) tirzepatide reduced body weight and fat content vs pair-fed controls by increasing white adipose lipolysis and enhancing...

Zhang A, Liu Q, Xiong Y, et al. Tirzepatide reduces body weight by increasing fat utiliza... Source

Full findingIn male mice, intracerebroventricular (i.c.v.) tirzepatide reduced body weight and fat content vs pair-fed controls by increasing white adipose lipolysis and enhancing thermogenesis in brown and beige adipose tissue, lowering respiratory exchange ratio (increased lipid utilisation). Effects were mediated by sympathetic nervous system innervation of adipose tissue, associated with neuronal activity changes in the dorsomedial hypothalamus and nucleus of the solitary tract.

PopulationChow- or HFD-fed male mice; single/long-term i.c.v. tirzepatide vs vehicle, with pair-fed control; metabolic cages (RER)

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitsanimal data; human relevance uncertain

Comparatorsvehicle; pair-fed control

Tirzepatide MARKETED

Energy expenditure and thermogenesis Increase

Very low evidence

In a mouse model of postmenopausal metabolic dysfunction (obese-diabetic +/- ovariectomy), tirzepatide reversed BAT 'whitening', restored multilocular brown adipocyte...

Bittencourt JOA, Marcondes-de-Castro IA, Marinho TS, Aguila MB, Mandarim-de-Lacerda CA. T... Source

Full findingIn a mouse model of postmenopausal metabolic dysfunction (obese-diabetic +/- ovariectomy), tirzepatide reversed BAT 'whitening', restored multilocular brown adipocyte morphology, and increased thermogenic markers including UCP1 and the beta3-adrenergic receptor; it reversed suppression of thermogenic and mitochondrial-fusion genes and normalised ER-stress/autophagy markers. Three-way ANOVA identified tirzepatide as the most potent regulator of the BAT gene landscape. It also reduced relative BAT mass by 25%.

PopulationFemale mice; control sham, control-OVX, obese-diabetic, obese-diabetic-OVX; 12 wk OVX/HFHS diet then 4 wk tirzepatide

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitsanimal data; human relevance uncertain

Comparatorscontrol sham; obese-diabetic untreated; ovariectomy groups

Mazdutide INVESTIGATIONAL

Energy expenditure and thermogenesis Increase

Low evidence

Glucagon-receptor arm proposed to increase energy expenditure and improve hepatic fat metabolism (mammalian OXM analogue)

Sidrak WR et al. Indian J Endocrinol Metab 2024;28:445-460 Source

PopulationMechanistic / review framing

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitsEE claim mechanistic; cross-ref cognition/EE preclinical PMID:40479843

Comparatorsdulaglutide (preclinical)

Survodutide INVESTIGATIONAL

Energy expenditure and thermogenesis Increase

Very low evidence

Weight loss driven by increased energy expenditure plus reduced food intake (preclinical)

Zimmermann T et al. Mol Metab 2022;66:101633 Source

PopulationMouse obesity models (preclinical pharmacology)

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitsEE mechanism preclinical; human EE not directly quantified

Comparatorssemaglutide

Most represented records

Evidence spread