From white to beige: a new hypothalamic pathway

Abstract

Understanding how brown and beige adipocytes can be differentially controlled and activated by neuronal circuits is a fundamental prerequisite to fully comprehend the metabolic role that fat tissue plays in energy homeostasis. In this issue of EMBO reports, Wang et al 1 identify a new hypothalamic route that drives the exclusive recruitment of beige fat via the selective control of sympathetic nervous system (SNS) outflow to subcutaneous white adipose tissue. Since the data strongly suggest that the APPL2–AMPK signaling axis is crucial for this activation, this finding sheds a new light on the cross talk between peripheral homeostatic signals and neurons that are part of hypothalamic energy homeostasis regulatory pathways in the ventromedial hypothalamus (VHM) proposing a new defending mechanism to cold and obesity.

Mammals, including adult humans, exhibit two types of fat, white adipose tissue (WAT) and brown adipose tissue (BAT). While WAT is best known for its role in fat storage, BAT is the key site of heat production (thermogenesis) through the action of specialized, heat‐producing adipocytes called brown adipocytes. Brown adipocytes conduct non‐shivering thermogenesis through BAT‐specific mitochondrial uncoupling protein 1 (UCP1). UCP1 mediates the proton influx generated by β‐oxidation of fatty acids back into the mitochondrial matrix and dissipates oxidative energy as heat instead of the synthesis of ATP. The capability of energy‐burning BAT provides a potential approach to increase caloric utilization and thus may be an attractive target to promote weight loss.

Such dichotomic difference between WAT and BAT is challenged by the fact that clusters of UCP1‐expressing adipocytes with thermogenic capacity also develop in WAT in response to different stimuli. These adipocytes named beige adipocytes show, similarly to adipocytes in BAT, the ability to undergo thermogenesis as well as a multilocular lipid droplet morphology, high mitochondrial content, and the expression of a core set of brown fat‐specific genes. However, whereas brown adipocytes express high levels of UCP1 and other thermogenic genes under unstimulated (basal) conditions, beige adipocytes express these genes only in response to activators such as agonists of the β‐adrenergic receptor or peroxisome proliferator‐activated receptor‐γ (Ppar‐γ) 2, 3.

The biomedical interest in brown and beige adipocytes has centered on the capacity of these cell types to counteract obesity via induction of energy expenditure and to mitigate the vast array of diseases associated with it, including type 2 diabetes, heart disease, insulin resistance, hyperglycemia, dyslipidemia, hypertension, and many types of cancer via paracrine and/or endocrine manners in several mouse models 4. In fact, increased activities of brown and beige adipocytes have been linked to obesity resistance in many mouse models. For many years, it was assumed that BAT was mainly present in small infants and human infants and thus not able to affect body weight in adults. However, in 2009, imaging studies revealed active substantial BAT in adult humans. Adult humans showed increased BAT activity during cold exposure, but decreased BAT activity when they are overweight or obese 5. Currently, the key and incisive question is to understand and define the different regulation of beiging and thermogenic programs in BAT and WAT under different nutritional and environmental events.

Thermogenesis highly depends on the sympathetic nervous system (SNS). Beige and brown adipocytes are richly innervated as evidenced by thyroxin hydroxylase‐positive cells, and also highly express the β3‐adrenoreceptor, a Gs protein‐coupled receptor primarily involved in thermogenesis. The release of noradrenaline (NA) by SNS efferent postganglionic fibers and the binding of this transmitter to the β3‐adrenergic receptors lead to a cascade of metabolic events triggering substrate oxidation and ultimately heat production. Mechanistically, the release of NA enhances brown adipocyte thermogenic activity (heat production as such) by increasing cyclic adenosine monophosphate (cAMP) levels, which in turn activates the protein kinase A (PKA) and the ultimate generation (through lipolysis) of fatty acids that serve as energy substrate and UCP1 activators. In addition, enhanced SNS activity also increases BAT thermogenic capacity (number of brown adipocytes, the quantity of mitochondria per adipocyte, expression of UCP1, and accompanying thermogenic proteins). Importantly, conditions such as cold exposure (cold‐induced thermogenesis) and feeding (diet‐induced thermogenesis) are integrated by the central nervous system (CNS) to stimulate brown adipocyte thermogenesis. In addition, β3‐adrenergic agonists also promote the “beiging” of WAT, which currently represents a major focus of attention among investigators studying the central control of thermogenesis 6.

In this issue, Wang et al 1 characterize a neural population in the ventromedial hypothalamus (VMH) and the underlying neural pathway that drives the recruitment of beige fat via a selective control of SNS outflow to subcutaneous WAT without affecting BAT. By employing both genetic models and pharmacogenetic approaches, they demonstrate that the activation of a specific subset of rat insulin promoter (RIP)‐Cre neurons in the VMH is able to convert energy‐storing white adipocytes to energy‐burning beige adipocytes in response to cold exposure but not fasting (Fig 1). RIP‐Cre neurons selectively control SNS outflow and beiging of subcutaneous WAT without affecting other tissues or having an impact on food intake. It remains, however, unknown whether RIP‐Cre neurons in the VMH control SNS outflow to WAT directly or indirectly via intrahypothalamic connections or neurotransmitters.

Figure 1. Schematic of hypothalamic route that promotes the development of beige fat via control of sympathetic nervous system (SNS) outflow to subcutaneous white adipose tissue.

See text for more details.

Ventromedial hypothalamus was the first hypothalamic site identified to regulate adaptive thermogenesis, and several studies back in the 1980s showed that electrical stimulation of the VMH increased body temperature in rats. VMH lesions/electrical stimulations were further demonstrated to affect BAT turnover, indicative of a mobilization of the autonomic nervous system 7. VMH integrates many signals such as thyroid hormone, estrogen, and GLP‐1 that could modulate SNS‐mediated BAT or WAT thermogenesis via the inhibition of AMP‐activated protein kinase (AMPK) 8, 9. In their study, Wang et al 1 propose a new model characterized by the disruption of the proper function of RIP‐Cre neurons in the VMH through APPL2 deletion.

Of note is that APPL2 was previously described as an adaptor protein, which acts in concert with APPL1 and negatively controls insulin or adiponectin‐stimulated glucose uptake in skeletal muscle and pancreatic β‐cells 9, 10. The deletion of APPL2 in the hypothalamus led to activation of AMPK with the consequent reduction of SNS outflow to sWAT and adaptive thermogenesis. Collectively, the data suggested that APPL2 was essential for cold and diet‐induced adaptive thermogenesis but not for starvation response. Definitively, further studies are needed to understand the critical regulation and interaction between APPL2 and AMPK and whether the APPL2–AMPK signaling axis is important for other thermogenic factors in the VMH since APPL2 senses and integrates many hormonal and peripheral signals and could critically control the homeostatic modulation of VMH neurons in BAT‐ or WAT‐induced thermogenesis.

EMBO Reports (2018) 19: e45928 29581171