Abstract
SummaryThe obesity epidemic is a significant global health issue. Improved understanding of the mechanisms that regulate appetite and body weight will provide the rationale for the design of anti-obesity therapies. Thyroid hormones play a key role in metabolic homeostasis through their interaction with thyroid hormone receptors (TRs), which function as ligand-inducible transcription factors. The TR-beta isoform (TRβ) is expressed in the ventromedial hypothalamus (VMH), a brain area important for control of energy homeostasis. Here, we report that selective knockdown of TRβ in the VMH of adult mice results in severe obesity due to hyperphagia and reduced energy expenditure. The observed increase in body weight is of a similar magnitude to murine models of the most extreme forms of monogenic obesity. These data identify TRβ in the VMH as a major physiological regulator of food intake and energy homeostasis.
Highlights
Energy homeostasis is regulated by neurotransmitters and by humoral factors including thyroid hormones, which act within the hypothalamus and systemically to regulate food intake (Coppola et al, 2007; Coll et al, 2007) and energy expenditure (Kim, 2008)
Tissue-Specific Knockdown of TR-beta isoform (TRb) in the ventromedial hypothalamus (VMH) in Adult Mice We knocked down TRb in the VMH of adult male mice using Cre-mediated excision of a floxed critical exon in the Thrb gene
Cre recombinase was introduced into the VMH of adult male Thrbflox/flox mice by stereotaxic injection of recombinant adeno-associated virus expressing a Cre-GFP fusion protein to generate mice with reduced TRb expression in the VMH (VMH-TRbÀ) mice
Summary
Energy homeostasis is regulated by neurotransmitters and by humoral factors including thyroid hormones, which act within the hypothalamus and systemically to regulate food intake (Coppola et al, 2007; Coll et al, 2007) and energy expenditure (Kim, 2008). Mice with heterozygous dominantnegative mutations of TRa display a variety of metabolic phenotypes ranging from hypermetabolism, hyperphagia, and resistance to diet-induced obesity (Sjogren et al, 2007) to increased visceral adiposity, hypophagia, and impaired cold-induced adaptive thermogenesis (Liu et al, 2003). Humans with RTHb may be overweight and hyperphagic (Mitchell et al, 2010) despite features of hyperthyroidism such as tachycardia and raised energy expenditure due to T3 actions in TRa-responsive tissues. These extensive studies demonstrate that thyroid hormone is an essential regulator of food intake and energy expenditure. Clinical and global gene targeting studies cannot differentiate between the developmental and adult, or systemic and central, effects of thyroid hormones
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