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 AMPKα1 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.

Objective: Glycerol constitutes an important metabolite for the control of lipid accumulation and glucose homeostasis. The impact of obesity and obesity-associated type 2 diabetes as well as the potential regulatory role of insulin and leptin on aquaglyceroporins (AQP) 3, 7, and 9 were analyzed. Research Design and Methods: The tissue distribution and expression of AQP in biopsies of omental and sc adipose tissue as well as liver were analyzed in lean and obese Caucasian volunteers (n = 63). The effect of insulin (1, 10, and 100 nmol/liter) and leptin (0.1, 1, and 10 nmol/liter) on the expression of the glycerol channels was determined in vitro in human omental adipocytes and HepG2 hepatocytes. The translocation of AQP in response to insulin and isoproterenol was analyzed by immunocytochemistry. Results: In addition to the well-known expression of AQP7 in adipose tissue, AQP3 and AQP9 were also expressed in both omental and sc adipose tissue. Obese type 2 diabetes patients showed higher expression of AQP in visceral adipose tissue and lower expression of AQP7 in sc adipose tissue and hepatic AQP9. The staining of AQP9 in the plasma membrane of adipocytes was reinforced by insulin, whereas isoproterenol induced the translocation of AQP3 and AQP7 from the lipid droplets to the plasma membrane. Insulin up-regulated all AQP, whereas leptin up-regulated AQP3 and down-regulated AQP7 and AQP9 in adipocytes and hepatocytes. These effects were abrogated by both the phosphatidylinositol 3-kinase inhibitor wortmannin and the mammalian target of rapamycin inhibitor rapamycin. Conclusions: Our findings show, for the first time, that insulin and leptin regulate the AQP through the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway in human visceral adipocytes and hepatocytes. AQP3 and AQP7 may facilitate glycerol efflux from adipose tissue while reducing the glycerol influx into hepatocytes via AQP9 to prevent the excessive lipid accumulation and the subsequent aggravation of hyperglycemia in human obesity.

Adiponectin is a member of the family of adipose tissue-related hormones known as adipokines, which exerts antidiabetic, antiatherogenic, antiinflammatory, and antiangiogenic properties. Adiponectin actions are primarily mediated through binding to two receptors expressed in several tissues, AdipoR1 and AdipoR2. Likewise, adiponectin expression has been detected in adipocytes as well as in a variety of extra-adipose tissues, including the chicken pituitary. Interestingly, adiponectin secretion and adiponectin receptor expression in adipocytes have been shown to be regulated by pituitary hormones. These observations led us to investigate whether adiponectin, like the adipokine leptin, regulates pituitary hormone production. Specifically, we focused our analysis on somatotrophs and gonadotrophs because of the relationship between the control of energy metabolism, growth and reproduction. To this end, the effects of adiponectin on both GH and LH secretion as well as its interaction with major stimulatory regulators of somatotrophs (ghrelin and GHRH) and gonadotrophs (GnRH) and with their corresponding receptors (GHS-R, GHRH-R, and GnRH-R), were evaluated in rat pituitary cell cultures. Results show that adiponectin inhibits GH and LH release as well as both ghrelin-induced GH release and GnRH-stimulated LH secretion in short-term (4 h) treated cell cultures, wherein the adipokine also increases GHRH-R and GHS-R mRNA content while decreasing that of GnRH-R. Additionally, we demonstrate that the pituitary expresses both adiponectin and adiponectin receptors under the regulation of the adipokine. In sum, our data indicate that adiponectin, either locally produced or from other sources, may play a neuroendocrine role in the control of both somatotrophs and gonadotrophs.