An international research team have discovered how to activate brown fat in humans, which may lead to new treatments for type 2 diabetes and obesity.
The results of the collaboration between the Centre de recherche du Centre hospitalier universitaire de Sherbrooke (CRCHUS) and the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen were published today in Cell Metabolism.
Brown fat burns energy and generates heat – a process called thermogenesis – after being activated by cold temperature or chemical signals.
Humans have small deposits of brown fat, and scientists have long hypothesized that finding alternative ways to pharmacologically activate the fat could help improve metabolism.
Scientists have now discovered that beta2-adrenergic receptors (b2-AR) in brown fat cells are responsible for stimulating thermogenesis.
According to Dr. Denis Blondin from CRCHUS, the finding could explain why most clinical trials, which have attempted to induce BAT to burn energy, have performed poorly.
“We show that perhaps we were aiming for the wrong target all along.
In contrast to rodents, human BAT is activated through the stimulation of the beta2-adrenergic receptor, the same receptor responsible for the release of fat from our white adipose tissue.”
Unlocking the therapeutic potential of brown fat
According to Associate Professor Camilla Schéele at CBMR, this finding has clear therapeutic applications.”Activation of brown fat burns calories, improves insulin sensitivity and even affects appetite regulation.
Our data reveals a previously unknown key to unlocking these functions in humans, which would potentially be of great gain for people living with obesity or type 2 diabetes”.
A second phase of research will begin in the autumn, which will attempt to validate the finding by activating brown fat with drugs that target b2-AR, explains Professor André Carpentier from CRCHUS:
“Our next step will be to use a drug that specifically activate that target on brown fat and determine how much it could be of use to burn fat and calories in humans.
Once this is done, studies in patients with type 2 diabetes will start to determine if this approach can be useful to improve the metabolic control of the disease.”
Obesity and type II diabetes are reaching pandemic proportions worldwide. Understanding the mechanisms underlying disturbed glucose and lipid metabolism is thus of great interest for efforts to identify new therapeutic targets for the treatment of these disorders.
Experimental studies have shown that impaired brown adipose tissue (BAT) activity is associated with obesity and insulin resistance. Conversely, highly active BAT is associated with a healthy metabolic phenotype that is generally attributed to the capacity of BAT to dissipate metabolic energy as heat through uncoupling protein 1 (UCP1)-mediated uncoupled mitochondrial oxidation1. In rodents, in addition to anatomically defined BAT sites that arise during ontogeny, brown adipocytes of distinct cellular origin, termed beige or brite, appear in white adipose tissue (WAT) depots after persistent thermogenic activation in the organism, a phenomenon referred to as browning or beiging of WAT2. This type of brown adipocyte appears to be the one that predominates in adult humans3. Genetic studies in rodents attribute an especially relevant role of the beiging process to protection against obesity4.
Recent findings suggest that the biological function of BAT might not be restricted to the unique function of energy consumption, and reports based on experimental BAT transplantation point to a role for this tissue as a source of endocrine signaling and release the so-called brown adipokines or batokines5,6. Given the very distinct functions of WAT and BAT in energy metabolism, it would be reasonable to expect that the profile of batokines released by BAT would be different from adipokines released by WAT. Our laboratory recently conducted a study aimed at discovering new potential molecules secreted by BAT, based on microarray and RNAseq data in BAT combined with bioinformatic prediction of secretability. Two candidate genes—Cxcl14, a recently characterized chemokine released by BAT7, and Kng (kininogen)—were identified. The kallikrein–kinin system, of which Kng is a part, is a complex hormonal signaling system with reported involvement in inflammation, blood pressure control, coagulation, and pain8. Because of alternative splicing, Kng encodes two different proteins: a high-molecular-weight Kng (HMWK) and a low-molecular-weight Kng (LMWK)9. In the human genome, only one gene (KNG1) has been described to date, whereas the mouse genome possesses a second gene, Kng2, in addition to Kng110. These two murine genes have a sequence identity of ~89%. The liver is considered the main site of KNG proteins production. Once HMWK is produced and released into the bloodstream, it is targeted by plasmatic kallikrein protease, yielding the active peptide bradykinin. In contrast, LMWK is cleaved by tissue kallikrein, releasing the active kallidin into the blood11. Bradykinin and kallidin are considered to act as vasodilators and target many cell types by activating the kinin B2 (B2) receptor, which is constitutively expressed in cells. Bradykinin and kallidin are ultimately cleaved again to produce the peptides, [Des-Arg9]-bradykinin/kallidin; these peptides act on the kinin B1 (B1) receptor, whose expression is induced by distinct stimuli, including inflammation8. A summary of these pathways is shown in Fig. 1a.
Very few reports to date have indicated a role for the kinin system in systemic metabolic regulation and adipose tissue biology. One group proposed that a B1 receptor deficiency leads to leptin hypersensitivity and resistance to obesity12.
A subsequent study from the same group suggested that kinin B1 and B2 receptor deficiencies improve glucose tolerance and have a protective role against high-fat-diet-induced obesity in mice13.
To date, however, no studies describing a role for Kng in BAT functions or secretory properties have been reported. Here, we identify KNG2 as a component of thermogenic stimulus-induced BAT adaptations and describe a key role for the kallikrein–kinin system in adipose tissue plasticity in response to thermogenic challenges.
In the present study, we identified Kng as a factor released by brown adipocytes in response to a thermogenic, noradrenergic-mediated stimulus. Although the kallikrein–kinin system is a poorly understood hormonal system, the limited available research points to a role in inflammation, blood pressure control, coagulation and pain8.
To date, however, there has been no evidence supporting a role for this system in brown adipose tissue-related processes of adaptive energy expenditure. Here, we demonstrate that the kallikrein–kinin system is involved in the control of BAT activation and recruitment, and plays an inhibitory role in the thermogenic function of brown fat (see scheme in Fig. 10d).
We found that Kng2 is the Kng gene that is preferentially expressed in BAT from mice. Expression of the Kng2 gene and release of the encoded proteins is stimulated by a cAMP-mediated, β3-adrenergic–induced regulatory mechanism, in concert with the thermogenic activation of BAT and thermogenic-induced browning of WAT.
A strong regulatory role for the kallikrein–kinin system in BAT in the context of thermogenic stimuli is reinforced by the intense reciprocal regulation between thermogenic activation and expression of the kinin receptors B1 and B2, occurring at least at transcript levels.
Despite our observation that a noradrenergic-mediated thermogenic stimulus increased blood KNG2 levels in mice in concert with induction of Kng2 expression specifically in BAT (and in the browning-prone iWAT depot), our various experimental interventions in the kallikrein–kinin system point to major effects in BAT itself rather than direct systemic effects.
In rats defective for KNG secretion, the most remarkable feature found was upregulation of BAT activity; similarly, BAT overactivation was systematically observed in mice with pharmacological or genetic disruption of the kinin receptor system.
These results are in line with our findings of inhibitory effects of Kng and bradykinin on thermogenic activation of brown adipocytes. Therefore, our findings identify a repressive action on thermogenic activity as the major effect of kallikrein–kinin signals that act upon BAT.
The fact that a thermogenic stimulus (i.e., cold) results in the enhanced release of a biological signal (Kng), that exerts suppressive effects on thermogenic activity may seem counter-intuitive at first glance, but it is not unique to the kallikrein–kinin system.
Additional examples of such behavior include several brown adipocyte secreted factors such as sLR11 (a soluble relative of the low-density lipoprotein receptor)30, endothelin A31, endocannabinoids32 and probably myostatin33.
Along with these molecules, Kng may play a role in an autocrine-based homeostatic mechanism that prevents excessive wasting of energy upon thermogenic activation, as previously proposed to explain this type of effect30.
Although relatively few studies relating the kallikrein–kinin system with energy metabolism, it has been reported that systemic pharmacological blockade of B1 reduces adiposity and improves the metabolic profile in rats34,35.
Moreover, a deficiency of kinin receptors in mice protects against high-fat-diet-induced obesity and improves glucose tolerance12,13 through mechanisms that do not involve changes in food intake, observations that are consistent with our demonstration of a repressive role of the kallikrein–kinin system on BAT activity.
In most settings, we found parallel WAT browning and BAT activation responses to kallikrein–kinin loss-of-function experimental strategies. However, in two of our experimental models—local effects of kinin receptor antagonists on WAT and response to cold in B1B2R-KO mice—blocking bradykinin action led to impaired browning in WAT.
The reason for these apparently discrepant observations is unclear. In our in vitro studies, we found repressive effects due to bradykinin signaling in brown adipocytes as well as in cells induced to differentiate into beige adipocytes, but not in white adipocytes.
We cannot rule out the possibility that the induction of BAT activity elicited by kinin receptor invalidation represses the extent of WAT browning owing to reciprocal compensatory processes similar to those reported in other mouse models36,37.
However, our experimental data in cell culture point to a potential cell-autonomous differential role of the kallikrein–kinin system on WAT and BAT.
It is worth mentioning that our in vivo experimental models based on thermal challenges did not allow us to unequivocally establish whether central effects of the kallikrein–kinin system38 are also involved in controlling of brown fat activity.
Our observation that upregulation of UCP1 in models of kallikrein–kinin loss-of-function is accompanied by increased tyrosine hydroxylase, indicative of enhanced sympathetic innervation, suggest that experimental suppression of the kallikrein–kinin system elicits a global remodeling of sympathetic innervation of BAT.
However, the enhanced activity of BAT in mice devoid of kinin receptors after pharmacological stimulation with a β3-adrenoceptor agonist indicates the intrinsically enhanced thermogenic capacity of BAT when kinin signaling is impaired does not rely on acute central signaling.
Accordingly, we found that bradykinin can repress the thermogenic machinery of brown adipocytes in a cell-autonomous manner through its action on bradykinin receptors.
Bradykinin appears to interfere with the β3-adrenergic induction of thermogenic activation in brown adipocytes through mechanisms involving the Gi subtype of G-protein-coupled receptors; this results in the inhibition of protein kinase-A activity and p38-MAPkinase, which are the main canonical intracellular actors that mediate the induction of Ucp1 gene transcription induction and overall of thermogenic activation29.
Such a mechanism is reminiscent of some, but not all, previous findings that have reported decreased cAMP levels in response to the activation of kinin receptors in other non-adipose cellular targets39.
However, it has also been reported that activation of kinin receptors may either increase40 or fail to modify41 cAMP levels, depending on the cell type under study. Further research is warranted to explore the molecular basis of this distinct cell-specific responsiveness to bradykinin.
In summary, we have identified a previously unsuspected pathway for controlling BAT thermogenic activity mediated by the kallikrein–kinin system, which is likely to act as an autocrine, autoregulatory mechanism in response to a thermogenic stimulus.
This finding may contribute to expanding the range of potential pharmacological candidates in therapeutic strategies against obesity and associated diseases designed to improve energy expenditure and remove excess blood metabolites through activation of BAT.
REFERENCE LINK : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195474/
More information: Denis P. Blondin et al, Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation, Cell Metabolism (2020). DOI: 10.1016/j.cmet.2020.07.005