Thyroid Hormone Receptor Beta in the Ventromedial Hypothalamus Is Essential for the Physiological Regulation of Food Intake and Body Weight

摘要

class="head no_bottom_margin" id="sec1title">IntroductionEnergy homeostasis is regulated by neurotransmitters and by humoral factors including thyroid hormones, which act within the hypothalamus and systemically to regulate food intake (, ) and energy expenditure (). The effects of the active form of thyroid hormone, 3,5,3′-l-triiodothyronine (T3), are mediated by two thyroid hormone receptors (TRα and TRβ), encoded by Thra and Thrb, respectively ().Metabolic phenotypes have been described in mice and humans with TR mutations. Mice with heterozygous dominant-negative mutations of TRα display a variety of metabolic phenotypes ranging from hypermetabolism, hyperphagia, and resistance to diet-induced obesity () to increased visceral adiposity, hypophagia, and impaired cold-induced adaptive thermogenesis (). The variation in described phenotypes is likely to be due to the differing actions of individual mutant receptors on wild-type TR function (). Humans with heterozygous dominant-negative mutations of TRα (resistance to thyroid hormone α [RTHα]) may be overweight or obese with reduced energy expenditure (, , ). Humans with heterozygous dominant-negative mutations of TRβ have RTHβ, resulting in high levels of circulating thyroid hormones and thyroid-stimulating hormone (TSH) due to impaired negative feedback of the hypothalamic-pituitary-thyroid axis (). Humans with RTHβ may be overweight and hyperphagic () despite features of hyperthyroidism such as tachycardia and raised energy expenditure due to T3 actions in TRα-responsive tissues. These extensive studies demonstrate that thyroid hormone is an essential regulator of food intake and energy expenditure. Despite this, clinical and global gene targeting studies cannot differentiate between the developmental and adult, or systemic and central, effects of thyroid hormones.The ventromedial hypothalamus (VMH) is a critical region of the brain involved in energy homeostasis. TRβ is the predominant TR isoform expressed in the VMH (, ), and previous studies suggest that thyroid hormones acting in the VMH regulate both food intake () and energy expenditure (href="#bib20" rid="bib20" class=" bibr popnode">López et al., 2010). Thus, we hypothesize that, in the VMH, TRβ physiologically regulates food intake and body weight. To investigate this hypothesis directly, we used stereotaxic Cre-lox gene targeting to generate a VMH-specific model of TRβ knockdown in adult mice.