Preclinical Assessment of Leptin Transport into the Cerebrospinal Fluid in Diet‐Induced Obese Minipigs

Abstract

Objective A minipig model was employed to explore the changes in endogenous leptin transport into the central nervous system and in hypothalamic sensitivity to exogenous leptin when individuals are placed on high‐fat diet (HFD) compared with standard diet. Methods Serum and cerebrospinal fluid (CSF) leptin concentrations during 10 weeks of HFD versus standard diet and exogenous leptin‐induced STAT3 phosphorylation in the hypothalamus of minipigs were assessed, and the hypothalamic leptin‐sensitive cells were characterized by immunofluorescence. Results The efficiency of the passage of endogenous blood‐borne leptin into the CSF (measured as the log [CSF:serum leptin ratio]) decreased over time in minipigs fed a HFD (β = –0.04 ± 0.005 per kilogram of weight gain in HFD; P < 0.0001), while it remained stable in minipigs fed a standard diet. However, the ability of peripherally administered leptin to activate its receptor in hypothalamic neurons was preserved in obese minipigs at 10 weeks of HFD. Conclusions Together, these data are consistent with the existence of an early‐onset tranport deficiency for endogenous circulating leptin into the brain in individuals developing obesity, preceding the acquisition of hypothalamic leptin resistance. Although additional studies are required to identify the underlying mechanisms, our study paves the way for the development of new preclinical pharmacological models targeting the restoration of the shuttling of peripheral leptin into the central nervous system to manage obesity.

Leptin brain entry via a tanycytic LepR–EGFR shuttle controls lipid metabolism and pancreas function

“…Increased food intake after overnight feeding ( Figure 3E ) despite elevated adiposity ( Figure 3G , 3I ) and circulating leptin levels in LepR TanKO mice ( Figure 3O ) raised the possibility that these animals could be developing hypothalamic resistance to circulating leptin, associated with defective leptin transport by tanycytes, as seen early in diet-induced obesity in various animal models 23 , 37 . First, to confirm that this phenomenon occurs under physiological conditions, we assessed endogenous STAT3 activation in the ARH, a surrogate for endogenous LepR activation 22 , 38 , at lights-on after overnight feeding, when circulating leptin levels are at their highest 39 .…”

Glial endozepines and energy balance: Old peptides with new tricks

“…Altogether, these results support the view that glial endozepines exert their anorexigenic effect, at least in part, by enhancing leptin entry into the hypothalamus (Figure 2). Because circulating leptin shuttling into the hypothalamus is shut down in animal models with diet‐induced obesity (Balland et al, 2014; Chmielewski et al, 2019) and in obese patients (Caro et al, 1996; Schwartz, Peskind, Raskind, Boyko, & Porte, 1996), OP‐promoted leptin transport by tanycytes may hold therapeutic potential for treating obesity. However, the hypothesis of a specific LepR‐ERK‐dependent tanycytic shuttle for leptin has recently been challenged.…”