Metabolic Profiling of the Hypothalamus of Mice during Short-Term Food Deprivation

Abstract

Nutrient availability and utilization in hypothalamic cells are directly associated with the regulation of whole-body energy homeostasis. Thus, establishing metabolic profiling in the hypothalamus in response to metabolic shift is valuable to better understand the underlying mechanism of appetite regulation. In the present study, we evaluate the alteration of lipophilic and hydrophilic metabolites in both the hypothalamus and serum of fasted mice. Fasted mice displayed an elevated ketone body and decreased lactate levels in the hypothalamus. In support of the metabolite data, we further confirmed that short-term food deprivation resulted in the altered expression of genes involved in cellular metabolic processes, including the shuttling of fuel sources and the production of monocarboxylates in hypothalamic astrocytes. Overall, the current study provides useful information to close the gap in our understanding of the molecular and cellular mechanisms underlying hypothalamic control of whole-body energy metabolism.

Whole Transcriptome Analysis of Hypothalamus in Mice during Short-Term Starvation

“…Among the 45 upregulated genes, we identified the ones that encode metabolic enzymes, such as Hmgcs2, which is involved in the synthesis of ketone bodies. In accordance with these findings, our previous studies indicated that the hunger-promoting condition triggered by fasting led to an increase in ketone bodies and a decrease in lactate in the hypothalamus, while mice retaining anorexigenic responses to lipopolysaccharide treatment revealed a contradicting pattern in the circulating levels of ketone bodies and lactate [ 32 , 33 ]. Circulating factors derived from peripheral organs, such as fat, muscle, and liver, dynamically act as signal messengers that propagate information on the current status of energy availability to integrating centers, such as the hypothalamus.…”

Glucagon-like peptide-1 analog liraglutide leads to multiple metabolic alterations in diet-induced obese mice

“…Liraglutide mimicked caloric restriction in mice, resulting in dramatic anorexia and weight loss in our study and others ( 20 , 21 , 36 ). Several metabolomic studies on caloric restriction using a very low-calorie diet, a fasting-mimicking diet, or fasting identified metabolomic signatures in the serum and liver ( 62 , 63 , 64 , 65 , 66 , 67 , 68 ). Caloric restrictions using these diets or acute fasting markedly increased 3-hydroxybutyric acid, a ketone body, in the serum and liver of both NCD and HFD mice ( 62 , 63 , 64 , 65 , 66 ).…”

“…Several metabolomic studies on caloric restriction using a very low-calorie diet, a fasting-mimicking diet, or fasting identified metabolomic signatures in the serum and liver ( 62 , 63 , 64 , 65 , 66 , 67 , 68 ). Caloric restrictions using these diets or acute fasting markedly increased 3-hydroxybutyric acid, a ketone body, in the serum and liver of both NCD and HFD mice ( 62 , 63 , 64 , 65 , 66 ). Interestingly, our data showed that liraglutide increased 3-hydroxybutyric acid in the liver but not in the plasma of HFD mice.…”

“…Interestingly, our data showed that liraglutide increased 3-hydroxybutyric acid in the liver but not in the plasma of HFD mice. Caloric restrictions using either a very low-calorie diet or a fasting-mimicking diet decreased the levels of isoleucine, valine, and proline in the serum and glycine and taurine in the liver under both NCD and HFD ( 62 , 65 , 66 , 67 ). In contrast, our study showed that liraglutide increased the levels of those amino acids in the plasma and liver of HFD mice, respectively.…”