The molecular motor
dynein is regulated by the
huntingtin protein, and
Huntington's disease (HD) mutations of huntingtin disrupt
dynein motor activity. Besides abnormalities in the central nervous system, HD animal models develop prominent peripheral pathology, with defective brown tissue thermogenesis and dysfunctional white adipocytes, but whether this peripheral phenotype is recapitulated by
dynein dysfunction is unknown. Here, we observed prominently increased adiposity in mice harboring the legs at odd angles (Loa/+) or the Cramping mutations (Cra/+) in the
dynein heavy chain gene. In Cra/+ mice, hyperadiposity occurred in the absence of energy imbalance and was the result of impaired
norepinephrine-stimulated lipolysis. A similar phenotype was observed in 3T3L1 adipocytes upon chemical inhibition of
dynein showing that loss of functional
dynein leads to impairment of lipolysis. Ex vivo,
dynein mutant adipose tissue displayed increased
reactive oxygen species production that was, at least partially, responsible for the decreased cellular responses to
norepinephrine and subsequent defect in stimulated lipolysis.
Dynein mutation also affected
norepinephrine efficacy to elicit a thermogenic response and led to morphological abnormalities in brown adipose tissue and cold intolerance in
dynein mutant mice. Interestingly,
protein levels of huntingtin were decreased in
dynein mutant adipose tissue. Collectively, our results provide genetic evidence that
dynein plays a key role in lipid metabolism and thermogenesis through a modulation of oxidative stress elicited by
norepinephrine. This peripheral phenotype of
dynein mutant mice is similar to that observed in various animal models of HD, lending further support for a functional link between huntingtin and
dynein.