Neonatal leptin antagonism improves metabolic programming of postnatally overnourished mice.

BACKGROUND/OBJECTIVES: Alteration of the perinatal nutritional environment is an important risk factor for the development of metabolic diseases in later life. The hormone leptin plays a critical role in growth and development. Previous studies reported that postnatal overnutrition increases leptin secretion during the pre-weaning period. However, a direct link between leptin, neonatal overnutrition, and lifelong metabolic regulation has not been investigated. METHODS: We used the small litter mouse model combined with neonatal leptin antagonist injections to examine whether attenuating leptin during early life improves lifelong metabolic regulation in postnatally overnourished mice. RESULTS: Postnatally overnourished mice displayed rapid weight gain during lactation and remained overweight as adults. These mice also showed increased adiposity and perturbations in glucose homeostasis in adulthood. Neonatal administration of a leptin antagonist normalized fat mass and insulin sensitivity in postnatally overnourished mice. These metabolic improvements were associated with enhanced sensitivity of hypothalamic neurons to leptin. CONCLUSIONS: Early postnatal overnutrition causes metabolic alterations that can be permanently attenuated with the administration of a leptin antagonist during a restricted developmental window.

The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling.

Uncertainty exists as to whether the glucose-dependent insulinotropic polypeptide receptor (GIPR) should be activated or inhibited for the treatment of obesity. Gipr was recently demonstrated in hypothalamic feeding centers, but the physiological relevance of CNS Gipr remains unknown. Here we show that HFD-fed CNS-Gipr KO mice and humanized (h)GIPR knockin mice with CNS-hGIPR deletion show decreased body weight and improved glucose metabolism. In DIO mice, acute central and peripheral administration of acyl-GIP increases cFos neuronal activity in hypothalamic feeding centers, and this coincides with decreased body weight and food intake and improved glucose handling. Chronic central and peripheral administration of acyl-GIP lowers body weight and food intake in wild-type mice, but shows blunted/absent efficacy in CNS-Gipr KO mice. Also, the superior metabolic effect of GLP-1/GIP co-agonism relative to GLP-1 is extinguished in CNS-Gipr KO mice. Our data hence establish a key role of CNS Gipr for control of energy metabolism.

Functional identity of hypothalamic melanocortin neurons depends on Tbx3.

Heterogeneous populations of hypothalamic neurons orchestrate energy balance via the release of specific signatures of neuropeptides. However, how specific intracellular machinery controls peptidergic identities and function of individual hypothalamic neurons remains largely unknown. The transcription factor T-box 3 (Tbx3) is expressed in hypothalamic neurons sensing and governing energy status, whereas human TBX3 haploinsufficiency has been linked with obesity. Here, we demonstrate that loss of Tbx3 function in hypothalamic neurons causes weight gain and other metabolic disturbances by disrupting both the peptidergic identity and plasticity of Pomc/Cart and Agrp/Npy neurons. These alterations are observed after loss of Tbx3 in both immature hypothalamic neurons and terminally differentiated mouse neurons. We further establish the importance of Tbx3 for body weight regulation in Drosophila melanogaster and show that TBX3 is implicated in the differentiation of human embryonic stem cells into hypothalamic Pomc neurons. Our data indicate that Tbx3 directs the terminal specification of neurons as functional components of the melanocortin system and is required for maintaining their peptidergic identity. In summary, we report the discovery of a key mechanistic process underlying the functional heterogeneity of hypothalamic neurons governing body weight and systemic metabolism.