LR11 is a neuronal apolipoprotein E (APOE) receptor implicated in the pathogenesis of Alzheimer’s disease, potentially through its dual function in vesicular trafficking [1]. There is also evidence that a portion of the LR11 peptide is proteolytically cleaved and this enters the nucleus to regulate transcription [2]. We observed that mice lacking LR11 were less susceptible to diet induced obesity and that LR11 expression was reduced in response to high fat diet feeding, suggesting a potential role for LR11 in energy balance. Methods: Wild type and LR11-/- C57Bl6/J mice were housed at either 21°C or thermoneutrality (30°C) and fed high fat diet (HFD) from 8 weeks old. Adipose tissues were collected at sacrifice. Indirect calorimetry (MetaTrace – Creative Scientific UK) was performed after 8 weeks of diet administration and adipose tissues were explanted at sacrifice for gene expression analysis (TaqMan – ABI). In a parallel study primary preadipocytes were extracted from wild type and LR11-/- mice aged 8 weeks old for differentiation in vivo and characterisation of thermogenic gene profiles. Similarly, immortalised brown adipocytes from a C57Bl6/J murine cell line were transfected with control and LR11 over-expression vectors (pCDNA – Promega) and differentiated for 8 days in vitro before gene expression profiling. Results: LR11-/- mice showed reduced weight gain compared to wild type mice when housed at thermoneutrality (28 g ± 2.2 g vs 44g ± 2.5g, p < 0.05) and were found to be hypermetabolic (30 j/min ± 0.8 vs 27.5 j/min ± 0.75, p < 0.05), a phenotype which was not observed at lower environmental temperatures. Expression of thermogenic genes was significantly increased in brown adipose tissue (BAT) and subcutaneous white adipose tissue (WAT) depots. Conversely, LR11 overexpression in a BAT cell line repressed expression of thermogenic genes and transcription factors. LR11 expression was also found to be negatively regulated in the hypothalamus in response to high fat diet feeding and cold exposure in wild type animals. Conclusions: LR11 acts as a negative regulator of thermogenesis in brown and subcutaneous adipose tissues. Downregulation of LR11 allows increased thermogenic gene expression and increased energy expenditure, conferring protection from diet-induced obesity. In vivo, this effect is independent of adrenergic stimulation as it penetrates the phenotype only at thermoneutrality, where sympathetic stimulation of BAT is absent. These results highlight LR11 as a new player in the regulation of thermogenic capacity in conditions more translatable to the human living environment (thermoneutrality) and suggest an additional mechanism of brown fat regulation.