Hypothalamic neuronal activation in primates drives naturalistic goal-directed eating behavior

Abstract

Eating addiction is the primary cause of modern obesity. Although the causal role of the lateral hypothalamic area (LHA) for eating is demonstrated in rodents, there is no evidence in primates regarding naturalistic eating behaviors. We investigated the role of LHA GABAergic (LHAGABA) neurons in eating by chemogenetics in three macaques. LHAGABA neuron activation significantly increased naturalistic goal-directed behaviors and food motivation, which was specific for palatable food. PET and MRS validated the chemogenetic activation. Rs-fMRI result revealed that functional connectivity (FC) between the LHA and frontal areas was increased, while the FC between the frontal cortices was decreased after the LHAGABA neuron activation. Thus, our study elucidates the role of LHAGABA neurons in eating and obesity therapeutics for primates and humans.

Tesofensine, a novel antiobesity drug, silences GABAergic hypothalamic neurons

“…However, the group treated with 5-HTP/CB exhibited a marked weight loss tolerance in subsequent days and began regaining body weight afterward. Unexpectedly, tesofensine (at both doses) prolonged the weight loss induced by 5-HTP and completely blocked the body weight tolerance (or body weight rebound) over the following days (Fig 8A, see days [7][8][9][10][11][12][13][14][15]. This suggests that tesofensine may have two components: one anorexigenic and a second that stimulates energy expenditure, the latter perhaps mediated by its NE component [2,61].…”

“…The LH comprises two major neuronal populations, GABAergic and glutamatergic neurons, that play opposing and bidirectional roles in reward and feeding [8][9][10]. In mice and primates, activation of LH GABA neurons promotes food intake, while silencing them inhibits food intake [11][12][13]. In contrast, in mice, the activation of LH glutamatergic neurons inhibits food intake, while their inhibition promotes food intake [10].…”