sirolimus and Hyperphagia

The protein leverage hypothesis predicts that low dietary protein should increase energy intake and cause adiposity. We designed 10 diets varying from 1% to 20% protein combined with either 60% or 20% fat. Contrasting the expectation, very low protein did not cause increased food intake. Although these mice had activated hunger signaling, they ate less food, resulting in decreased body weight and improved glucose tolerance but not increased frailty, even under 60% fat. Moreover, they did not show hyperphagia when returned to a 20% protein diet, which could be mimicked by treatment with rapamycin. Intracerebroventricular injection of AAV-S6K1 significantly blunted the decrease in both food intake and body weight in mice fed 1% protein, an effect not observed with inhibition of eIF2a, TRPML1, and Fgf21 signaling. Hence, the 1% protein diet induced decreased food intake and body weight via a mechanism partially dependent on hypothalamic mTOR signaling.

Topics: Activating Transcription Factor 4; Adipose Tissue, White; Animals; Diet, Protein-Restricted; Eating; Energy Metabolism; Fibroblast Growth Factors; Gene Expression; Glucose Tolerance Test; Hyperphagia; Hypothalamus; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Weight Loss

Given the increasing prevalence of and severity of complications associated with obesity, there is great need for treatments resulting in prolonged weight loss. Long-term maintenance of weight loss requires sustained changes in food-intake and energy-expenditure strategies, which are unfortunately often taxing, resulting in a return to predieting weight. Therefore, drug therapies may facilitate greater adherence to a restricted diet and prolong weight loss. One such drug is rapamycin (RAP), a mechanistic target of rapamycin (mTOR) inhibitor. Here, we show that a single injection of RAP dampens the hyperphagic response in calorically restricted rats when they are returned to free feed immediately or 10 days after injection. Moreover, we demonstrate that a single injection of RAP given to calorically restricted rats prevents body-weight regain when animals are returned to free feed either immediately or 10 days after injection. Furthermore, we extend our previous findings that RAP does not produce malaise or illness and show that RAP does not produce any behavioral deficits that may inhibit an animal from eating. Thus, we suggest that mTOR may be a useful target in obesity research, given that its inhibition may decrease the hyperphagic response following caloric restriction. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Topics: Affect; Animals; Caloric Restriction; Eating; Hyperphagia; Male; Rats, Sprague-Dawley; Sirolimus; Weight Gain

Hypothalamic AMP-activated protein kinase (AMPK) plays important roles in the regulation of food intake by altering the expression of orexigenic or anorexigenic neuropeptides. However, little is known about the mechanisms of this regulation. Here, we report that hypothalamic AMPK modulates the expression of NPY (neuropeptide Y), an orexigenic neuropeptide, and POMC (pro-opiomelanocortin-α), an anorexigenic neuropeptide, by regulating autophagic activity in vitro and in vivo. In hypothalamic cell lines subjected to low glucose availability such as 2-deoxy-d-glucose (2DG)-induced glucoprivation or glucose deprivation, autophagy was induced via the activation of AMPK, which regulates ULK1 and MTOR complex 1 followed by increased Npy and decreased Pomc expression. Pharmacological or genetic inhibition of autophagy diminished the effect of AMPK on neuropeptide expression in hypothalamic cell lines. Moreover, AMPK knockdown in the arcuate nucleus of the hypothalamus decreased autophagic activity and changed Npy and Pomc expression, leading to a reduction in food intake and body weight. AMPK knockdown abolished the orexigenic effects of intraperitoneal 2DG injection by decreasing autophagy and changing Npy and Pomc expression in mice fed a high-fat diet. We suggest that the induction of autophagy is a possible mechanism of AMPK-mediated regulation of neuropeptide expression and control of feeding in response to low glucose availability.

Topics: AMP-Activated Protein Kinases; Animals; Arcuate Nucleus of Hypothalamus; Autophagy; Autophagy-Related Protein 5; Autophagy-Related Protein-1 Homolog; Body Weight; Cell Line; Deoxyglucose; Down-Regulation; Eating; Enzyme Activation; Gene Expression Regulation; Gene Knockdown Techniques; Hyperphagia; Hypothalamus; Male; Mechanistic Target of Rapamycin Complex 1; Mice, Inbred C57BL; Multiprotein Complexes; Neuropeptide Y; Pro-Opiomelanocortin; RNA, Messenger; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Up-Regulation

Hyperthyroidism is characterized in rats by increased energy expenditure and marked hyperphagia. Alterations of thermogenesis linked to hyperthyroidism are associated with dysregulation of hypothalamic AMPK and fatty acid metabolism; however, the central mechanisms mediating hyperthyroidism-induced hyperphagia remain largely unclear. Here, we demonstrate that hyperthyroid rats exhibit marked up-regulation of the hypothalamic mammalian target of rapamycin (mTOR) signalling pathway associated with increased mRNA levels of agouti-related protein (AgRP) and neuropeptide Y (NPY), and decreased mRNA levels of pro-opiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC), an area where mTOR co-localizes with thyroid hormone receptor-α (TRα). Central administration of thyroid hormone (T3) or genetic activation of thyroid hormone signalling in the ARC recapitulated hyperthyroidism effects on feeding and the mTOR pathway. In turn, central inhibition of mTOR signalling with rapamycin in hyperthyroid rats reversed hyperphagia and normalized the expression of ARC-derived neuropeptides, resulting in substantial body weight loss. The data indicate that in the hyperthyroid state, increased feeding is associated with thyroid hormone-induced up-regulation of mTOR signalling. Furthermore, our findings that different neuronal modulations influence food intake and energy expenditure in hyperthyroidism pave the way for a more rational design of specific and selective therapeutic compounds aimed at reversing the metabolic consequences of this disease.

Topics: Agouti-Related Protein; AMP-Activated Protein Kinases; Animals; Disease Models, Animal; Eating; Feeding Behavior; Hyperphagia; Hyperthyroidism; Hypothalamus; Male; Neural Pathways; Neuropeptide Y; Phosphorylation; Pro-Opiomelanocortin; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Sirolimus; Thyroid Hormone Receptors alpha; Time Factors; TOR Serine-Threonine Kinases; Triiodothyronine; Weight Loss

The mammalian target of rapamycin (mTOR) promotes anabolic cellular processes in response to growth factors and metabolic cues. The TSC1 and TSC2 tumor suppressors are major upstream inhibitory regulators of mTOR signaling. Mice with Rip2/Cre-mediated deletion of Tsc1 (Rip-Tsc1cKO mice) developed hyperphagia and obesity, suggesting that hypothalamic disruption (for which Rip2/Cre is well known) of Tsc1 may dysregulate feeding circuits via mTOR activation. Indeed, Rip-Tsc1cKO mice displayed increased mTOR signaling and enlarged neuron cell size in a number of hypothalamic populations, including Pomc neurons. Furthermore, Tsc1 deletion with Pomc/Cre (Pomc-Tsc1cKO mice) resulted in dysregulation of Pomc neurons and hyperphagic obesity. Treatment with the mTOR inhibitor, rapamycin, ameliorated the hyperphagia, obesity, and the altered Pomc neuronal morphology in developing or adult Pomc-Tsc1cKO mice, and cessation of treatment reinstated these phenotypes. Thus, ongoing mTOR activation in Pomc neurons blocks the catabolic function of these neurons to promote nutrient intake and increased adiposity.

Topics: Animals; Energy Metabolism; Gene Deletion; Hyperphagia; Hypothalamus; Melanocortins; Mice; Mice, Knockout; Neurons; Obesity; Pro-Opiomelanocortin; Protein Kinases; Receptor-Interacting Protein Serine-Threonine Kinase 2; Receptor-Interacting Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins