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

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 (ß = -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.

["Norms and autonomy. Southern German clinical psychiatrists' strategies of legitimation and power of interpretation in the first half of the 19th century"]. / Norm und Autonomie. Legitimierungsstrategien und Deutungsmacht süddeutscher Anstaltspsychiater in der ersten Hälfte des 19. Jahrhunderts.

In the present article the Southern German states of Baden and Bavaria are analyzed to exemplify the ways in which during the first half of the 19th century clinical psychiatrists advanced to experts and how they gained within and outside the institutional sphere a psychiatric sovereignty of interpretation ("psychiatrische Deutungsmacht"). One aspect in this development are strategies with which their position as physician was legitimized and ensured. Another aspect analyzed are the conditions under which physicians were able to act. It is to be noted that the rise of the psychiatric profession took place in two phases: Up until the 1820s, during the so called establishing phase of institutional psychiatry, the physician's active horizont was limited to the clinical sphere. Then, a process of "professional self-discovery" set in. Only with the institutional differentiation from the 1830s onwards, clinical psychiatrists also began to appear outside the clinics as experts and critical councellors. However, the fact that there was a gradual gain in autonomy and the establishment of a psychiatric sovereignty of interpretation also within state bureaucracy cannot be explained solely by tendencies toward professionalization. It was rather a multilayered process involving different participants and vested interests. The role of the state is of special importance: Motivated by its interest in solving the problem of deviance through medicalization, the state not only helped to bring institutional psychiatry into being, but also paved the way for the rise of clinical psychiatry.