Adipose tissue in obesity
Obesity is defined by the World Health Organisation (WHO) as ‘abnormal
or excessive fat accumulation that may impair health.’ In horses we have
yet to define this parameter, so our definition of obesity is based
solely on measures of subcutaneous fat. We do know that in obese horses,
as defined by BCS, adipose can account for up to 35% of body mass
(Dugdale et al, 2012).
Obese adipose tissue, particularly VAT, is markedly dysfunctional in
humans and directly related to the development of obesity associated
morbidities including insulin resistance and cardiovascular risk
(Santillana et al., 2023). In horses, dysfunction of obese adipose
tissue is also clear. Reynolds et al (2019) found marked
hypertrophy of VAT adipocytes, a hallmark of dysfunctional adipose in
humans. Fibrosis, a key feature of human dysregulated adipose, was not
found in the adipose of these horses but has been reported by others
(Basinska et al., 2015), this discrepancy perhaps due to the chronicity
of disease in the animals studied. Dysfunctional adipose has also been
shown to have increased expression of leptin (Reynolds et al., 2019).
There is conflicting data regarding adipocytokine expression in obese
adipose of horses, as there is in the human literature. Whilst Burnset al (2010) showed no change in TNFα and IL1β in obese adipose
(Burns et al., 2010), several groups have since shown increases
associated with obesity and insulin dysregulation in VAT (Reynolds et
al., 2019; Jayathilake et al., 2022) and SAT (Basinska et al., 2015).
Basinska et al also reported macrophage infiltration. It should
be noted that the populations studied are invariably diverse in terms of
disease state. In humans, obese adipose expansion by hypertrophy fails
to stimulate angiogenesis which is driven by increased cell number
(hyperplasia), therefore the blood supply eventually becomes limited and
hypoxia occurs which contributes to inflammation (Hammarstedt et al.,
2018). Although this has not yet been investigated, the same process may
occur in the horse.
A key question in understanding how obesity results in insulin
resistance, is whether obese adipose tissue is itself insulin resistant.
There is currently not a clear answer to this question in humans as it
appears to be the case in some individuals but not in others. This
alludes to the increasing acceptance that many sub-types of insulin
resistance syndromes exist (Imi et al., 2023). Very little is known
about insulin sensitivity of obese adipose in horses. A crude measure of
insulin signalling components in adipose showed no differences between
lean horses and those with equine metabolic syndrome (Reynolds et al.,
2019); however, insulin signalling is dynamic and relies on an altered
phosphorylation state, so much more work is required in this area.
Figure Diagram showing some of the known and proposed effects of
unhealthy adipose tissue seen in overweight/obese patients. Created with
BioRender.com
The next question is whether dysfunctional obese adipose tissue
contributes to whole body insulin dysregulation. The answer is
invariably yes in human and rodent models, although there is still
debate over the temporal nature of this relationship (Blüher, 2016; Kahn
and Flier, 2000; Kahn et al., 2006). In general, it is thought that
factors released in greater or lesser quantities from obese adipose
perturb insulin signalling, whether that is a function of the insulin
receptor itself or the downstream signalling cascade, particularly in
liver and muscle but also in adipose. These downstream factors include
adipocytokines (Blüher, 2016), leptin and adiponectin (Yadav et al.,
2013). Overloaded adipocytes, especially in VAT, can release free fatty
acids into the portal circulation and overwhelm hepatic gluconeogenesis
thus impacting insulin sensitivity (Longo et al., 2019). If adipocytes
have reached capacity for safe storage then lipid will be deposited
ectopically such as in muscle and in liver which is detrimental to
insulin sensitivity in those tissues (Longo et al., 2019).