Weight Perturbation Alters Leptin Signal Transduction in a Region-Specific Manner throughout the Brain

Abstract

Diet-induced obesity (DIO) resulting from consumption of a high fat diet (HFD) attenuates normal neuronal responses to leptin and may contribute to the metabolic defense of an acquired higher body weight in humans; the molecular bases for the persistence of this defense are unknown. We measured the responses of 23 brain regions to exogenous leptin in 4 different groups of weight- and/or diet-perturbed mice. Responses to leptin were assessed by quantifying pSTAT3 levels in brain nuclei 30 minutes following 3 mg/kg intraperitoneal leptin. HFD attenuated leptin sensing throughout the brain, but weight loss did not restore central leptin signaling to control levels in several brain regions important in energy homeostasis, including the arcuate and dorsomedial hypothalamic nuclei. Effects of diet on leptin signaling varied by brain region, with results dependent on the method of weight loss (restriction of calories of HFD, ad lib intake of standard mouse chow). High fat diet attenuates leptin signaling throughout the brain, but some brain regions maintain their ability to sense leptin. Weight loss restores leptin sensing to some degree in most (but not all) brain regions, while other brain regions display hypersensitivity to leptin following weight loss. Normal leptin sensing was restored in several brain regions, with the pattern of restoration dependent on the method of weight loss.

Describing the Weight‐Reduced State: Physiology, Behavior, and Interventions

“…Therefore, these responses do not differ qualitatively or quantitatively among individuals with and without obesity. What differs among individuals is the threshold, and therefore leptin signal transduction is dependent upon an individual's "usual weight" and any ongoing or previous negative energy balance (78).…”

The Role of Leptin in the Development of Energy Homeostatic Systems and the Maintenance of Body Weight

“…What differs between individuals with and without obesity is the threshold. Therefore leptin signal transduction is dependent upon an individual's "usual weight" and any ongoing or previous negative energy balance (Morabito et al, 2017).…”

Leptin resensitisation: a reversion of leptin-resistant states

“…In particular, decreasing the dietary fat content in mice fed with HFD for 20 weeks reverses obesity and hypothalamic leptin sensitivity in the ARH after 7 weeks of diet switch (Enriori et al 2007). Another study showed that 12 weeks of low-fat diet after 30 weeks of DIO not only decreases body weight and leptinaemia to values similar to lean mice but also recovers leptin-induced pSTAT3 levels in some brain regions to a greater extent than energy restriction (Morabito et al 2017). However, ARH and DMH do not recover leptin sensitivity neither with energy restriction nor with dietary switch (Morabito et al 2017).…”

“…Fasting-induced decrease in leptinaemia is partly regulated by sympathetic outflow to the white adipose tissue regulating leptin biosynthesis and secretion (Caron et al 2018). Energy restriction also reduces leptinaemia and restores leptin-induced pSTAT3 response in several brain regions including VMH (Morabito et al 2017). Additionally, diet switch from HFD to regular chow reverses leptin resistance in some DIO models.…”

“…Another study showed that 12 weeks of low-fat diet after 30 weeks of DIO not only decreases body weight and leptinaemia to values similar to lean mice but also recovers leptin-induced pSTAT3 levels in some brain regions to a greater extent than energy restriction (Morabito et al 2017). However, ARH and DMH do not recover leptin sensitivity neither with energy restriction nor with dietary switch (Morabito et al 2017). Diet composition can also affect leptin resensitisation.…”