How the brain tips the scale

Obesity results from an imbalance in energy intake and energy expenditure (including basal metabolic rate, thermogenesis and physical activity). Weight loss through reduced dietary energy intake is the cornerstone of therapy for people with obesity but it is difficult to achieve. Pharmacological weight loss therapies are therefore much sought after. The central melanocortin receptor (MCR) system provides an attractive potential drug target for obesity prevention and treatment because it is essential in regulating energy balance both by promoting satiety and by increasing energy expenditure (Krashes et al. 2016). Moreover, targeting the MCR system circumvents impaired insulin‐ and leptin‐mediated second messenger signalling to MCRs that is characteristic of obesity (Schwartz, 2006). Peripheral positive energy balance signals (e.g. insulin and leptin) activate pro‐opiomelanocortin neurons in the arcuate nucleus which in turn releases melanocortins, most notably α‐melanocyte‐stimulating hormone (α‐MSH), that stimulate MCRs in the paraventricular hypothalamus and to some extent also the ventromedial hypothalamus (VMH) to inhibit food intake. Studies that employed central administration of MCR agonists and transgenic and knock‐out mouse models found that MCR signalling also increases energy expenditure but the mechanisms responsible for it are not entirely clear (Krashes et al. 2016). After cold exposure, MCR signalling in paraventricular hypothalamic and extrahypothalamic cholinergic preganglionic sympathetic neurons of the intermediolateral nucleus of the spinal cord increases sympathetic drive to brown adipose tissue (BAT) which in turn results in markedly increased BAT thermogenesis (Labbé et al. 2015; Krashes et al. 2016). However, the effect of even fully activated BAT thermogenesis on whole body energy expenditure is small (<5%), owing to the small amount of BAT, and cannot fully account for the changes in total energy expenditure in various experimental models that evaluated the effect of BAT thermogenesis on energy balance (Poekes et al. 2015; Krashes et al. 2016). Moreover, a significant proportion of persons with obesity apparently lack functional BAT, which limits the potential impact of BAT as a target for anti‐obesity pharmacotherapy (Poekes et al. 2015).

In this issue of The Journal of Physiology, Gavini, Jones and Novak performed an elegant series of studies that demonstrate that activation of MCRs in the VMH increases energy expenditure and fat oxidation via increased sympathetic drive‐mediated thermogenesis in skeletal muscles (Gavini et al. 2016). They administered melanotan II (MTII), an α‐MSH analogue, into the VMH of rats and found that it increases ambulatory activity, whole body oxygen consumption (energy expenditure), fat oxidation and muscle heat dissipation. To distinguish the contribution of increased ambulation from VMH MCR activation itself on energy expenditure, fat oxidation and muscle heat dissipation, they repeated this experiment in rats who walked on a treadmill at a fixed workload. They found that the VMH MTII‐induced increases in energy expenditure, fat oxidation and muscle heat dissipation persisted even when physical activity was controlled. The increase in muscle heat dissipation was accompanied by increased noradrenaline (norepinephrine) turnover, a marker of sympathetic drive, and increased expression of genes involved in thermogenesis and fatty acid oxidation in muscles. Administration of the β‐adrenergic signalling blocker nadolol decreased muscle heat dissipation. This study has thereby identified the VMH melanocortin system as a major regulator of whole body energy expenditure and fatty acid oxidation both through its effects on spontaneous physical activity and activity‐independent thermogenesis in muscle. These effects are likely specific to VMH MCR stimulation because previous studies have identified the VMH, but not other mediobasal hypothalamic regions, as the source of MCR‐stimulated sympathetic drive in skeletal muscle. Accordingly, the work by Gavini, Jones and Novak provides novel insights into the mechanisms for thermoregulation that could potentially be exploited to combat obesity through increasing thermogenesis in a large tissue mass. Nevertheless, there are several caveats to consider.

Figure 1. The ventromedial hypothalamic melanocortin system as regulator of energy balance .

Theoretical model of how melanocortin receptor signalling in the ventromedial hypothalamus contributes to leanness. MCR: melanocortin receptor. VMH: ventromedial hypothalamus.

Although the study by Gavini et al. (2016) provides compelling evidence that MCR activation acutely increases spontaneous physical activity, muscle thermogenesis and fat oxidation, the effect of chronic MCR activation on these outcomes remains unknown. Furthermore, the selectivity and specificity of newly designed MCR agonists are likely to be essential in the development of a clinically viable MCR agonist as anti‐obesity treatment. It has been demonstrated that MCR activation with non‐selective and selective (type 4) MCR agonists suppresses food intake in diet‐induced obese (DIO) rodents (Fani et al. 2014) whereas chronic MCR activation in DIO non‐human primates causes significant weight loss with some, but not all, MCR type 4 agonists (Kievit et al. 2013; Fani et al. 2014). In addition, the increase in futile heat production by muscle could have the unintended consequence of making physical activity harder (and ultimately potentially favour sedentary behaviour) by increasing the energy demand for muscle activity. Lastly, there is the concern of increased systemic sympathetic drive, including increased sympathetic drive to the vasculature and the heart, which could result in tachycardia and hypertension, and white adipose tissue, which results in increased lipolysis and could promote ectopic lipid accumulation if lipolysis and fatty acid oxidation are not tightly matched (Kievit et al. 2013; Fani et al. 2014).

In summary, the VMH MCR system is an important regulator of energy balance but to be a viable therapeutic target for pharmacological obesity intervention it will be critical to find out if selective MCR activation can discriminate sympathetic activation of skeletal muscle (to induce thermogenesis) and the cardiovascular system (to avoid the undesirable cardiovascular effects of chronic sympathetic outflow).

Additional information

Competing interests

None declared.

Funding

Julia Dunn was supported by a VA Career Development Award IK2 CX000943.