Activation of the hypothalamic-pituitary-adrenal axis by exogenous and endogenous GDF15.

An acute increase in the circulating concentration of glucocorticoid hormones is essential for the survival of severe somatic stresses. Circulating concentrations of GDF15, a hormone that acts in the brain to reduce food intake, are frequently elevated in stressful states. We now report that GDF15 potently activates the hypothalamic-pituitary-adrenal (HPA) axis in mice and rats. A blocking antibody to the GDNF-family receptor α-like receptor completely prevented the corticosterone response to GDF15 administration. In wild-type mice exposed to a range of stressful stimuli, circulating levels of both corticosterone and GDF15 rose acutely. In the case of Escherichia coli or lipopolysaccharide injections, the vigorous proinflammatory cytokine response elicited was sufficient to produce a near-maximal HPA response, regardless of the presence or absence of GDF15. In contrast, the activation of the HPA axis seen in wild-type mice in response to the administration of genotoxic or endoplasmic reticulum toxins, which do not provoke a marked rise in cytokines, was absent in Gdf15 -/- mice. In conclusion, consistent with its proposed role as a sentinel hormone, endogenous GDF15 is required for the activation of the protective HPA response to toxins that do not induce a substantial cytokine response. In the context of efforts to develop GDF15 as an antiobesity therapeutic, these findings identify a biomarker of target engagement and a previously unrecognized pharmacodynamic effect, which will require monitoring in human studies

Murine neuronatin deficiency is associated with a hypervariable food intake and bimodal obesity

Abstract: Neuronatin (Nnat) has previously been reported to be part of a network of imprinted genes downstream of the chromatin regulator Trim28. Disruption of Trim28 or of members of this network, including neuronatin, results in an unusual phenotype of a bimodal body weight. To better characterise this variability, we examined the key contributors to energy balance in Nnat+/−p mice that carry a paternal null allele and do not express Nnat. Consistent with our previous studies, Nnat deficient mice on chow diet displayed a bimodal body weight phenotype with more than 30% of Nnat+/−p mice developing obesity. In response to both a 45% high fat diet and exposure to thermoneutrality (30 °C) Nnat deficient mice maintained the hypervariable body weight phenotype. Within a calorimetry system, food intake in Nnat+/−p mice was hypervariable, with some mice consuming more than twice the intake seen in wild type littermates. A hyperphagic response was also seen in Nnat+/−p mice in a second, non-home cage environment. An expected correlation between body weight and energy expenditure was seen, but corrections for the effects of positive energy balance and body weight greatly diminished the effect of neuronatin deficiency on energy expenditure. Male and female Nnat+/−p mice displayed subtle distinctions in the degree of variance body weight phenotype and food intake and further sexual dimorphism was reflected in different patterns of hypothalamic gene expression in Nnat+/−p mice. Loss of the imprinted gene Nnat is associated with a highly variable food intake, with the impact of this phenotype varying between genetically identical individuals

Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance

Thyroid hormones (THs) act in the brain to modulate energy balance. We show that central triiodothyronine (T3) regulates de novo lipogenesis in liver and lipid oxidation in brown adipose tissue (BAT) through the parasympathetic (PSNS) and sympathetic nervous system (SNS), respectively. Central T3 promotes hepatic lipogenesis with parallel stimulation of the thermogenic program in BAT. The action of T3 depends on AMP-activated protein kinase (AMPK)-induced regulation of two signaling pathways in the ventromedial nucleus of the hypothalamus (VMH): decreased ceramide-induced endoplasmic reticulum(ER) stress, which promotes BAT thermogenesis, and increased c-Jun N-terminal kinase (JNK) activation, which controls hepatic lipid metabolism. Of note, ablation of AMPK alpha 1 in steroidogenic factor 1 (SF1) neurons of the VMH fully recapitulated the effect of central T3, pointing to this population in mediating the effect of central THs on metabolism. Overall, these findings uncover the underlying pathways through which central T3 modulates peripheral metabolism.Peer reviewe

Ghrelin in the regulation of feeding and energy balance

Ghrelin, the first identified endogenous ligand for the growth hormone secretagogue receptor 1A, is a 28 amino acid peptide produced mainly by the stomach. Pharmacological studies indicate a role for ghrelin in the regulation of growth hormone secretion from the pituitary and also in the regulation of body weight, fat accumulation and food intake. Using a classical endocrine deletion/replacement approach we found support for the notion that endogenous ghrelin is required for the maintenance of normal body weight and adiposity. Gastrectomy (Gx) surgery, that depleted animals of ~80% of circulating ghrelin, caused a reduction in body weight, fat mass and lean mass in adult mice. Ghrelin replacement (at a dose that restores circulating ghrelin levels in Gx mice and that is without effect on body weight in sham animals) fully or partially reversed the decrease in body weight, fat mass and lean mass following Gx. To further investigate the central mechanism behind these effects on body weight and fat mass following Gx-surgery and ghrelin treatment key hypothalamic genes involved in energy homeostasis were analysed by in situ hybridisation. Surprisingly the marked changes in body composition following Gx did not effect expression of the hypothalamic genes studied, to any large extent. By contrast ghrelin treatment increased mRNA expression of NPY and AgRP and decreased POMC mRNA expression in accordance with ghrelin s effects to increase fat mass and body weight. Using growth hormone receptor (GHR) knockout animals we investigated the importance of a functional GHR signalling system for the acute effects of ghrelin on food intake. Ghrelin treatment increased food intake in wild type animals but not in GHR knockouts indicating that a functional GHR signalling system is needed for the acute effects of ghrelin on food intake. In addition to impacting upon the hypothalamic circuits controlling energy balance, ghrelin was found to interact with the mesolimbic reward circuits (reflected by increased locomotor activity and dopamine release after ghrelin injection to the brain ventricles). In conclusion, endogenous ghrelin from the stomach is important for maintaining normal body weight and body composition. Long term treatment with ghrelin increases body fat by a mechanism that appears to be independent of its acute affects on food intake. Long term ghrelin treatment still impacts upon hypothalamic genes regulating energy balance. Ghrelin s acute effect on food intake is dependant on a functional GHR signalling system. Moreover, this effect may be linked to dopamine release in areas of the brain intimately associated with reward-seeking activities

Obesity-associated gene TMEM18 has a role in the central control of appetite and body weight regulation.

Significance The growing size and sophistication of genome-wide association studies have led to the identification of variants which are clearly and reliably associated with obesity. A strong association between increased BMI and a region of human chromosome 2, near to the gene TMEM18 , has been repeatedly demonstrated in children and adults. The function of TMEM18 in the control of appetitive behavior and body composition has been poorly characterized. In murine models, we show germline loss results in weight gain while adult onset hypothalamic overexpression results in weight loss, supporting the hypothesis that TMEM18 acting within the central nervous system can affect energy balance. We also report a structure and putative molecular function of TMEM18, challenging the current published model. </jats:p