CPT1C in the ventromedial nucleus of the hypothalamus is necessary for brown fat thermogenesis activation in obesity

Abstract

ObjectiveCarnitine palmitoyltransferase 1C (CPT1C) is implicated in central regulation of energy homeostasis. Our aim was to investigate whether CPT1C in the ventromedial nucleus of the hypothalamus (VMH) is involved in the activation of brown adipose tissue (BAT) thermogenesis in the early stages of diet-induced obesity.MethodsCPT1C KO and wild type (WT) mice were exposed to short-term high-fat (HF) diet feeding or to intracerebroventricular leptin administration and BAT thermogenesis activation was evaluated. Body weight, adiposity, food intake, and leptinemia were also assayed.ResultsUnder 7 days of HF diet, WT mice showed a maximum activation peak of BAT thermogenesis that counteracted obesity development, whereas this activation was impaired in CPT1C KO mice. KO animals evidenced higher body weight, adiposity, hyperleptinemia, ER stress, and disrupted hypothalamic leptin signaling. Leptin-induced BAT thermogenesis was abolished in KO mice. These results indicate an earlier onset leptin resistance in CPT1C KO mice. Since AMPK in the VMH is crucial in the regulation of BAT thermogenesis, we analyzed if CPT1C was a downstream factor of this pathway. Genetic inactivation of AMPK within the VMH was unable to induce BAT thermogenesis and body weight loss in KO mice, indicating that CPT1C is likely downstream AMPK in the central mechanism modulating thermogenesis within the VMH. Quite opposite, the expression of CPT1C in the VMH restored the phenotype.ConclusionCPT1C is necessary for the activation of BAT thermogenesis driven by leptin, HF diet exposure, and AMPK inhibition within the VMH. This study underscores the importance of CPT1C in the activation of BAT thermogenesis to counteract diet-induced obesity.

Melatonin multiple effects on brown adipose tissue molecular machinery

“…Brown adipose tissue metabolic challenges such as HFD exposure and cold exposure are known to activate heat production by this tissue. Nonshivering thermogenesis triggering was prevented in Ucp1 knock‐out mice exposed to high‐fat diet, showing that it is crucial for the proper BAT response, and chronic HFD exposure was able to increase both Ucp1 and Pgc1α gene expression and UCP1 protein expression in mice . Even though pinealectomy did not alter that, we observed that melatonin therapeutic replacement further increased Ucp1 gene expression after acute high‐fat diet exposure, suggesting that melatonin acts on BAT preparation to this metabolic challenge.…”

“…The evidences of active interscapular brown adipose tissue (BAT) in adults reignited the interest of the scientific community, mainly for its nonshivering thermogenesis . Cold exposure and hypercaloric diets are well‐known BAT activators, as well as T4 after local conversion to T3 by iodothyronine deiodinase type II (Dio2), which seems to increase BAT thermogenic capacity and recruitment …”

Hypothalamic C2-domain protein involved in MC4R trafficking and control of energy balance

“…Distinct neuronal circuits and signaling mechanisms within the brain, in particular, hypothalamus regulates energy balance (feeding and metabolism) through adjustments in physiological processes. Disruption of some of these hypothalamic mechanisms is thought to be involved in the obesity and had been targeted to improve energy balance homeostasis [7][8][9][10][11][12]. One such mechanism involves the melanocortin system.…”

AMPK in the Ventromedial Nucleus of the Hypothalamus: A Key Regulator for Thermogenesis

“…One acknowledged explanation is that AMPK alters cellular lipid composition by regulating its downstream mediator carnitine palmitoyltransferase 1 (CPT-1), resulting in elevated intracellular ceramide contents, which cause lipotoxicity and trigger the initiation of ER stress (52). In line with this observation, mice lacking CPT-1C display higher hypothalamic ER stress levels and body weight as well as impaired thermogenic response to shortterm HFD exposure (145). Given the fact that THs, GLP-1, E2, BMP8B and leptin all stimulate BAT thermogenesis by inhibiting AMPK within the VMH and the close relationship between hypothalamic AMPK and ER stress (16,52,64,66,114), the VMH AMPK-ER stress-BAT axis may represent a canonical pathway for multiple peripheral signals that act on the VMH to control thermogenesis, although more studies are needed to further testify this hypothesis.…”