Two back-to-back publications in Cell provide novel insights into the neuronal molecular mechanisms implicated in the control of whole-body energy balance and highlight a pivotal role of mitochondrial membrane proteins, the mitofusins, in these processes.

Mitochondria, the key organelles for energy production, act as a dynamic consortium undergoing fusion and fission. Two proteins that make up the mitochondrial outer membrane fusion machinery are mitofusin-1 and mitofusin-2. Mitochondrial dysfunctions have been associated with metabolic disorders. Moreover, mitofusin-2 in liver and skeletal muscle has been implicated in the pathophysiology of type 2 diabetes mellitus and obesity. The group of Tamas L. Horvath (Yale University School of Medicine, New Haven, USA) previously showed that, in mice, the number of mitochondria increases during fasting in AgRP neurons—a critical population of hypothalamic neurons implicated in appetite and body weight control. “We also showed that during high-fat feeding, AgRP neurons, instead of being silent, fire at a high rate. We wanted to understand the bioenergetics underlying these adaptive changes,” recounts Horvath.

Now, Horvath and his team were able to show in mice that a dynamic change occurs in the mitochondria of AgRP neurons under different metabolic conditions. The researchers also found that the number of mitochondria changes in the opposite direction in POMC neurons—a second population of hypothalamic neurons implicated in energy balance. Their findings also show that mitochondrial fusion is required for the electrical activity of AgRP neurons under high-fat feeding conditions. Eliminating fusion by cell-selective deletion of mitofusin-1 or mitofusin-2 lowered the firing rate of AgRP neurons, and animals gained less fat on a high-fat diet.

While Horvath focused predominantly on the mitochondrial dynamics in orexigenic AgRP neurons, a second group of researchers led by Marc Claret (Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain), in collaboration with Horvath, assessed the role of mitofusins in anorexigenic POMC neurons. Claret and co-workers observed that diet-induced obesity in mice led to a loss of interaction between mitochondria and the endoplasmic reticulum (ER) in POMC neurons. “Intriguingly, mitofusin-2 was known to tether these two organelles, so we thought that this protein could be an excellent candidate to mediate the alterations in mitochondria–ER contacts,” says Claret. Indeed, deletion of mitofusin-2 in POMC neurons caused early hypothalamic ER stress, leptin resistance, altered POMC processing, hyperphagia, reduced energy expenditure and obesity. Central delivery of chemical chaperones reversed the metabolic defects observed in this mouse model. Of note, loss of mitofusin-1 in POMC neurons did not alter energy balance, indicating specific and divergent roles for mitofusins.

Leptin resistance is a hallmark of obesity, but its neurobiological basis remains elusive. “This makes leptin resistance one of the long-lasting unsolved riddles in metabolic research,” comments Claret. “I think that one of the most significant contributions of our study is the involvement of mitofusin-2 in POMC neurons in ER-stress-induced leptin resistance. This novel and previously unrecognized molecular mechanism indicates that proper mitochondria–ER axis homeostasis and function is essential for the control of whole-body energy balance.”

The ultimate goal of any biomedical research project is to provide mechanistic insights that will lead to therapeutic applications in the future. However, the findings of these two studies also indicate that interference with mitochondria-related mechanisms in different cell types can have very diverse outcomes. “Thus, our observations suggest multiple adverse effects of therapeutics targeting mitochondrial dysfunction,” concludes Horvath.