**Absence of Uncoupling Protein-3 at Thermoneutrality Impacts Lipid Handling and Energy Homeostasis in Mice**

**Assunta Lombardi 1,\*,**†**, Rosa Anna Busiello 1,**†**, Rita De Matteis 2, Lillà Lionetti 3, Sabrina Savarese 1, Maria Moreno 4, Alessandra Gentile 1, Elena Silvestri 4, Rosalba Senese 5, Pieter de Lange 5, Federica Cio** ffi **4, Antonia Lanni 5 and Fernando Goglia 4,\***


Received: 27 June 2019; Accepted: 15 August 2019; Published: 17 August 2019

**Abstract:** The role of uncoupling protein-3 (UCP3) in energy and lipid metabolism was investigated. Male wild-type (WT) and UCP3-null (KO) mice that were housed at thermoneutrality (30 ◦C) were used as the animal model. In KO mice, the ability of skeletal muscle mitochondria to oxidize fatty acids (but not pyruvate or succinate) was reduced. At whole animal level, adult KO mice presented blunted resting metabolic rates, energy expenditure, food intake, and the use of lipids as metabolic substrates. When WT and KO mice were fed with a standard/low-fat diet for 80 days, since weaning, they showed similar weight gain and body composition. Interestingly, KO mice showed lower fat accumulation in visceral adipose tissue and higher ectopic fat accumulation in liver and skeletal muscle. When fed with a high-fat diet for 80 days, since weaning, KO mice showed enhanced energy efficiency and an increased lipid gain (thus leading to a change in body composition between the two genotypes). We conclude that UCP3 plays a role in energy and lipid homeostasis and in preserving lean tissues by lipotoxicity, in mice that were housed at thermoneutrality.

**Keywords:** uncoupling protein; mitochondria: energy metabolism; lipid handling; fatty acid oxidation
